Biosynthesis

Catecholamine synthesis begins with the amino acid tyrosine, which comes from the diet or via hydroxylation of phenylalanine in the liver. l-Tyrosine is converted to dihydroxyphenylalanine (dopa) by tyrosine hydroxylase (TH) (Fig. 14-2). This reaction requires molecular oxygen and the cofactor tetrahydrobiopterin and represents the rate-limiting step in catecholamine biosynthesis (Fig. 14-3).³² Tissue sources of catecholamines therefore are principally dependent on the presence of this enzyme, which is largely confined to dopaminergic and noradrenergic neurons of the central nervous system, and to sympathetic nerves and chromaffin cells of the adrenal medulla and extramedullary paraganglia in the periphery.

Dopa is decarboxylated by aromatic l-amino acid decarboxylase to produce dopamine. The dopamine formed in neurons and chromaffin cells is translocated from the cytoplasm into vesicular storage granules. In dopaminergic neurons of the central nervous system, dopamine serves as the end product neurotransmitter. Large amounts of dopamine are produced as an end product of catecholamine synthesis in peripheral non-neuronal cells of the gastrointestinal tract and kidneys.³³ The dopamine present in urine is derived mainly from decarboxylation of dopa taken up from the circulation by the kidneys.

The dopamine formed in noradrenergic neurons and chromaffin cells is converted to norepinephrine by dopamine β-hydroxylase (DBH), an enzyme that is found only in the vesicles of cells that synthesize norepinephrine and epinephrine.

In adrenal medullary chromaffin cells, norepinephrine is metabolized by the cytosolic enzyme phenylethanolamine N-methyltransferase (PNMT) to form epinephrine.³⁴ Epinephrine then is translocated into chromaffin granules, where the amine is stored while awaiting release.³⁵ PNMT activity is induced by high levels of glucocorticoid production in the adrenal cortex.

Presumably because expression of PNMT is dependent on high local concentrations of glucocorticoids, pheochromocytomas that produce large amounts of epinephrine typically have an adrenal location, whereas those in extra-adrenal locations usually produce only norepinephrine.³⁶ Pheochromocytomas that lack both PNMT and DBH and that predominantly produce dopamine are extremely rare. Dopamine production is a more common finding in individuals with parasympathetic-associated paragangliomas.

Conversion of tyrosine to dopa by TH represents the pivotal step in regulating synthesis and in maintaining stores of catecholamines in response to changes in catecholamine turnover associated with variations in exocytotic release. Rapid activation of TH is achieved by phosphorylation of serine residues at the regulatory domain, under the control of multiple Ca²⁺ and cyclic adenosine monophosphate (cAMP)-dependent pathways influenced by changes in nerve activity and actions of peptides and other coactivators.³⁷ Long-term regulation involves induction of synthesis of the enzyme at the transcriptional level. Feedback inhibition by catecholamines provides a further mechanism for the short-term regulation of enzyme activity.

α-Methyl-l-tyrosine or metyrosine (Demser) is an analogue of tyrosine that inhibits TH, thereby decreasing catecholamine stores. The drug is used occasionally in patients with pheochromocytoma (particularly those with extensive metastatic disease) or preoperatively.

Storage and Release

Translocation of catecholamines into vesicular granules for storage is facilitated by two vesicular monoamine transporters.³⁸ Both transporters have wide specificity for different monoamine substrates. It is important to note that vesicular stores of catecholamines do not exist in a static state, simply waiting for a signal for exocytotic release. Rather, vesicular stores of catecholamines exist in a highly dynamic equilibrium with the surrounding cytoplasm, with passive outward leakage of catecholamines into the cytoplasm counterbalanced by inward active transport under control of the vesicular monoamine transporters.³¹

Catecholamines share the acidic environment of the storage granule matrix with adenosine triphosphate (ATP), peptides, and proteins, the most well known of which are the chromogranins.³⁹ The chromogranins are ubiquitous components of secretory vesicles, and their widespread presence among endocrine tissues has led to their measurement in plasma as useful, albeit relatively nonspecific, markers of neuroendocrine tumors, including pheochromocytomas.

Catecholamines are stored in several types of vesicular granules that differ in size and type of protein and peptide components, the specific functions of which are incompletely understood. Two populations of chromaffin cells have been described with morphologically distinct vesicles, which preferentially store norepinephrine or epinephrine, and which release the two catecholamines differentially in response to different stimuli. Most adrenal pheochromocytomas secrete both norepinephrine and epinephrine; about a third exclusively produce norepinephrine, and a much smaller proportion exclusively produce and secrete epinephrine.

The process of exocytosis occurs at specialized locations on sympathetic varicosities dictated by the cell-surface expression of specialized docking proteins that interact with other proteins on the surfaces of secretory vesicles. The process is stimulated by an influx of Ca²⁺, which in neurons is controlled primarily by nerve impulse–mediated membrane depolarization, and in adrenal medullary cells by acetylcholine release from innervating splanchnic nerves. The wide range of voltage-, receptor-, G protein–, and second messenger–operated Ca²⁺ channels provide numerous points for regulation of Ca²⁺-triggered exocytosis. In this way, a variety of peptides, neurotransmitters, and humoral factors provide additional mechanisms for stimulation of exocytosis or may act to modulate nerve impulse–stimulated release of catecholamines. Norepinephrine also inhibits its own release through occupation of presynaptic α₂-adrenoceptors. The mechanisms regulating catecholamine release are closely coordinated so as to regulate the enzymes responsible for synthesis, thereby ensuring appropriate replenishment of the catecholamines lost through exocytosis.⁴⁰

Uptake and Metabolism

Because the enzymes responsible for the metabolism of catecholamines have intracellular locations, the primary mechanism limiting the life span of catecholamines in the extracellular space is uptake by active transport, not metabolism by enzymes.⁴¹ Uptake is facilitated by transporters that belong to two families with mainly neuronal and extraneuronal locations. The neuronal norepinephrine transporter provides the principal mechanism for rapid termination of the signal in sympathoneuronal transmission, whereas transporters at extraneuronal locations are more important for limiting the spread of the signal and for clearing catecholamines from the bloodstream. For norepinephrine released by sympathetic nerves, about 90% is removed back into nerves by neuronal uptake, 5% is removed by extraneuronal uptake, and 5% escapes these processes to enter the bloodstream. In contrast, for epinephrine released directly into the bloodstream from the adrenals, about 90% is removed by extraneuronal monoamine transport processes, the liver being particularly important. The presence of these highly active transport processes means that catecholamines are rapidly cleared from the bloodstream with a circulatory half-life of less than 2 minutes.

Irreversible inactivation of released catecholamines occurs in a series arrangement, with uptake followed by metabolism. Metabolism occurs through a multiplicity of pathways catalyzed by an array of enzymes and resulting in a variety of metabolites (see Figs. 14-3 and 14-4).⁴² Deamination of catecholamines by monoamine oxidase (MAO) yields reactive aldehyde intermediate metabolites that are metabolized further to deaminated acids (by aldehyde dehydrogenase) or to deaminated alcohols (by aldehyde or aldose reductase). The aldehyde intermediate formed from dopamine is a good substrate for aldehyde dehydrogenase but not for aldehyde or aldose reductase. In contrast, the aldehyde intermediates formed from the β-hydroxylated catecholamines (i.e., norepinephrine and epinephrine) are good substrates for aldehyde or aldose reductase but are poor substrates for aldehyde dehydrogenase. Therefore, norepinephrine and epinephrine are preferentially deaminated to 3,4-dihydroxyphenylglycol (DHPG), the alcohol metabolite. Deamination to the deaminated acid metabolite, 3,4-dihydroxymandelic acid (DHMA), is not a favored pathway.

Catechol-O-methyltransferase (COMT) is responsible for the second major pathway of catecholamine metabolism: catalyzing O-methylation of dopamine to methoxytyramine, norepinephrine to normetanephrine, and epinephrine to metanephrine. COMT is not present in catecholamine-producing neurons, which contain exclusively MAO, but it is present along with MAO in most extraneuronal tissues. The membrane-bound isoform of COMT, which has high affinity for catecholamines, is especially abundant in adrenal chromaffin and pheochromocytoma tumor cells.⁴³ As a result of differences in expression of metabolizing enzymes, catecholamines produced in neurons and adrenal medullary or pheochromocytoma tumor cells follow different neuronal and extraneuronal pathways of metabolism (see Figs. 14-3 and 14-4).

Neuronal pathways are quantitatively far more important than are extraneuronal pathways for the metabolism of norepinephrine produced in sympathetic nerves (see Fig. 14-4). The reasons for this are twofold. First, much more norepinephrine released by sympathetic nerves is removed by neuronal uptake than by extraneuronal uptake. Second, under resting conditions, much more of the norepinephrine metabolized intraneuronally is derived from transmitter leaking from storage vesicles than from transmitter recaptured after exocytotic release. Thus, most of the norepinephrine produced in the body is metabolized initially to DHPG, mainly from transmitter deaminated intraneuronally after leakage from storage vesicles or after release and reuptake.

DHPG is further O-methylated by COMT in non-neuronal tissues to 3-methoxy-4-hydroxyphenylglycol (MHPG), a metabolite that is also produced to a limited extent by deamination of normetanephrine and metanephrine. Compared with DHPG, normetanephrine and metanephrine are produced in small amounts and only at extraneuronal locations, with the single largest source representing adrenal chromaffin cells, which account for more than 90% of circulating metanephrine and 24% to 40% of circulating normetanephrine.⁴⁴ Within the adrenals, normetanephrine and metanephrine are produced similarly to DHPG in sympathetic nerves, from norepinephrine and epinephrine leaking from storage granules into the chromaffin cell cytoplasm.

The MHPG produced from DHPG and metanephrines is conjugated or metabolized to vanillylmandelic acid (VMA) by the sequential actions of alcohol dehydrogenase and aldehyde dehydrogenase. The former enzyme is localized largely to the liver. Thus, at least 90% of the VMA formed in the body is produced in the liver, mainly from hepatic uptake and metabolism of circulating DHPG and MHPG.⁴⁵

With the exception of VMA, all the catecholamines and their metabolites are metabolized to sulfate conjugates by a specific sulfotransferase isoenzyme type 1A3 (SULT1A3). In humans, a single amino acid substitution confers the enzyme with particularly high affinity for dopamine and the O-methylated metabolites of catecholamines, including normetanephrine, metanephrine, and methoxytyramine. The SULT1A3 isoenzyme is found in high concentrations in gastrointestinal tissues, which therefore represent a major source of sulfate conjugates.

In humans, VMA and the sulfate and glucuronide conjugates of MHPG represent the main end products of norepinephrine and epinephrine metabolism. HVA and the conjugates of HVA are the main metabolic end products of dopamine metabolism. These end products and the other conjugates are eliminated mainly by urinary excretion. As a result, their circulatory clearance is slow and their plasma concentrations are high relative to those of the precursor amines.

Signs and Symptoms

The presence of pheochromocytoma usually is characterized by clinical signs and symptoms (Table 14-1) that result from hemodynamic and metabolic actions of circulating catecholamines or, less commonly, of other amines and co-secreted neuropeptides.¹⁸ Clinical findings such as hypertension, headache, unusual sweating, frequent arrhythmias, and the presence of pallor during hypertensive episodes are highly suggestive of pheochromocytoma. Although headache, palpitations, and sweating are nonspecific symptoms, their presence in patients with hypertension should arouse immediate suspicion for a pheochromocytoma because this triad constitutes the most commonly encountered symptoms in patients with a pheochromocytoma.

Sustained or paroxysmal hypertension (equally present) is the most common clinical sign (85% to 90%). Up to 13% of patients typically present with persistently normal blood pressure,5,18 but this proportion can be much higher in patients with adrenal incidentalomas or in those who undergo periodic screening for familial pheochromocytoma.^12,46,47 In the latter group, tumors now are being found at an earlier stage, usually are quite small, and secrete low amounts of catecholamines. Other factors that may affect pheochromocytoma-associated elevations in blood pressure include the nature of catecholamine secretion, that is, receptor downregulation caused by consistently high levels of catecholamines, hypovolemia, and associated changes in sympathetic nerve function.⁴⁸ Pheochromocytoma also may present with hypotension, particularly with postural hypotension or with alternating episodes of high and low blood pressure.^5,49 This is commonly seen in patients who harbor tumors that are secreting epinephrine or compounds causing vasodilatation, or after higher doses of antihypertensive therapy. Hypotension also may occur secondary to hypovolemia, abnormal autonomic reflexes, or differential stimulation of α- and β-adrenergic receptors, or as a result of the type of neuropeptide that is co-secreted.

Headache, which occurs in up to 90% of patients with pheochromocytoma,1,18 may be mild or severe, short or long in duration, and may last for up to several days. In some patients, catecholamine-induced headache may be similar to tension headache.

Excessive generalized sweating occurs in approximately 60% to 70% of patients presenting with pheochromocytoma.1,18 Other complaints are palpitations and dyspnea, weight loss despite normal appetite (caused by catecholamine-induced glycogenolysis and lipolysis), and generalized weakness.^49,50

Some patients present with new and commonly more severe episodes of anxiety or panic attacks.⁴⁹ Palpitations, anxiety, and nervousness are more common in patients with pheochromocytomas that produce epinephrine.⁴⁹ Less common clinical manifestations include fever of unknown origin (hypermetabolic state) and constipation secondary to catecholamine-induced decrease in intestinal motility, or possibly enkephalins.⁵¹ Some patients say that they feel flushed^18,52; however, in our experience, the observation of an actual flush during a paroxysmal hypertensive episode in a patient with pheochromocytoma is an exceedingly rare event. Occasionally, Raynaud’s phenomenon is noted. Patients also may present with tremor, seizures, hyperglycemia, hypermetabolism, weight loss (usually noted only in patients with malignant pheochromocytoma), fever, and even mental changes.^18,52

Pheochromocytoma-induced metabolic or hemodynamic attacks may last from a few seconds to several hours, with intervals between attacks varying widely; some occur only once every few months. A typical paroxysm is characterized by a sudden major increase in blood pressure; a severe, often pounding headache; profuse sweating over most of the body, especially the trunk; palpitations with or without tachycardia; prominent anxiety or a sense of doom; skin pallor; nausea, with or without emesis; and pain in the abdomen, the chest, or both.18,52,53 After an episode, patients usually feel drained and exhausted, and some may urinate more frequently. Initially, the episodes may be mild, of short duration, and infrequent.

Unusual symptoms related to paroxysmal blood pressure elevations during diagnostic procedures such as endoscopy, administration of anesthesia (caused by a sudden fall in blood pressure or any activation of the sympathetic nervous system, such as occurs during the induction phase of general anesthesia), or ingestion of food or beverages containing tyramine (e.g., certain cheeses, beers, wines, bananas, and chocolate) should arouse immediate suspicion of pheochromocytoma. The use of certain drugs such as histamine, metoclopramide, adrenocorticotropic hormone (ACTH), phenothiazine, methyldopa, monoamine oxidase inhibitors, tricyclic antidepressants, opiates (e.g., morphine, fentanyl), naloxone, droperidol, metoclopramide, glucagon, and chemotherapy may precipitate a hypertensive episode.18,52,54–60 Moreover, micturition or bladder distention in the case of a pheochromocytoma of the urinary bladder (more than half of these individuals have painless hematuria) should promptly arouse suspicion of the presence of this tumor. Causes that account for episodic catecholamine secretion often remain unestablished, but in some situations, it may be caused by intentional or accidental tumor manipulation coupled with an increase in intra-abdominal pressure from palpation, defecation, a fall, an automobile accident, or pregnancy.^18,52,61 Psychological stress does not usually precipitate a hypertensive crisis.^18,52,61 Timing of attacks may be unpredictable, and attacks may also occur at rest. However, about 8% to 10% of patients may be completely asymptomatic, usually because of a very small (less than 1 cm) tumor associated with nonsignificant catecholamine secretion or tumor dedifferentiation characterized by the absence of catecholamine-synthesizing enzymes and resulting in no production of catecholamines.⁵ Normal plasma and urine catecholamines and metanephrines due to absence of catecholamine production have been observed in patients with metastatic pheochromocytoma, often due to an underlying mutation of the succinate dehydrogenase subunit B gene.⁶² The defect was identified as an absence of tyrosine hydroxylase, the enzyme that catalyzes the initial and rate-limiting step in catecholamine biosynthesis (personal communication). These patients with so-called biochemically silent pheochromocytoma usually present at an advanced stage of the disease with symptoms and signs related to tumor mass effects rather than with symptoms and signs of catecholamine excess.

The hyperglycemia is usually mild, occurs with the hypertensive episodes, is accompanied by a subnormal level of plasma insulin (because of α-adrenergic inhibition of insulin release),⁶³ and usually does not require treatment; however, it can be sustained and severe enough to require insulin and even to present as diabetic ketoacidosis.⁶⁴ Hypoglycemia has also been reported.

Hypercalcemia has been reported in some patients with pheochromocytoma, sometimes as part of multiple endocrine neoplasia type 2 (MEN2)⁵⁴ but at other times without evidence of parathyroid disease⁶⁵ because the hypercalcemia disappears after the tumor is resected. Likewise, high levels of serum calcitonin, suggestive of medullary thyroid carcinoma, have been reported; these return to normal after the tumor is removed.⁶⁶ In addition, pheochromocytoma has presented as Cushing’s syndrome with the tumor as the ectopic source of ACTH.⁶⁷ Because catecholamines suppress intestinal motility, constipation is common, and occasionally even adynamic ileus occurs. Rarely, pheochromocytoma has produced vasoactive intestinal peptide with resultant watery diarrhea, hypokalemia, and achlorhydria (Verner-Morrison syndrome).⁶⁸ Lactic acidosis without shock or sepsis has been reported.⁶⁹ Interleukin-6 (IL-6) may have caused fever and multiorgan failure in one patient with pheochromocytoma with increased serum IL-6 and in another with pheochromocytoma and Castleman’s disease (IL-6–mediated B cell proliferation) because these conditions were reversed in each patient when the tumor was removed.^70,71 Many patients with pheochromocytoma are asymptomatic or have only minor signs and symptoms; therefore, the diagnosis is easily missed, often with tragic consequences. Several studies of routine autopsies have indicated that most pheochromocytomas are first discovered after death.⁴ This pattern has continued into more recent studies, which show that the diagnosis is missed much more often in elderly patients.⁷² This may result from the fact that elderly patients often have other, more common diseases (e.g., coronary or cerebral atherosclerosis) that could easily explain the minor symptoms that patients report.⁷² A list of emergency situations characteristic for the presence of pheochromocytoma are described in Table 14-2.

Estrogen, growth hormone, vitamin D, and retinol A (Accutane) have been shown to induce pheochromocytoma in experimental animals.⁷³ Whether these hormones contribute to the higher incidence of clinical pheochromocytoma or to an increase in malignant potential is unknown; however, recently at least two patients chronically receiving Accutane treatment were found to have pheochromocytoma (personal communications).

In summary, the following patients should be evaluated for a pheochromocytoma: (1) anyone with the triad of headaches, sweating, and tachycardia, whether or not the subject has hypertension; (2) anyone with a known mutation of one of the susceptibility genes and/or a family history of pheochromocytoma; (3) anyone with an incidental adrenal mass; (4) anyone whose hypertension is associated with borderline increases in catecholamine production reflected by elevated plasma catecholamine or metanephrine levels; (5) anyone whose blood pressure is poorly responsive to standard therapy; and (6) anyone who has had hypertension, tachycardia, or an arrhythmia in response to anesthesia, surgery, or medications known to precipitate symptoms in patients with pheochromocytoma.⁴⁸

Differential Diagnosis

The differential diagnosis of pheochromocytoma includes a long list of conditions that may suggest the presence of the tumor (Table 14-3).^18,52,61 Many of these conditions can be excluded readily on the basis of a good history and physical examination. The most common mimic is hyperadrenergic hypertension, which is characterized by tachycardia, sweating, anxiety, and increased cardiac output.^74,75 These patients often have increased levels of catecholamines in blood and urine and may be excluded by use of the clonidine suppression test, which shows that the excess catecholamines are caused by excess central sympathetic nervous activity and are not caused by a tumor (see the following).⁴⁸ Another common problem involves differentiating patients with pheochromocytoma from those with anxiety or panic attacks. This generally requires close observation of the patient during an episode.

Differentiation from an acute myocardial infarction may be difficult because angina pectoris and myocardial damage may occur in the absence of coronary artery disease in a patient with a pheochromocytoma. Many nonspecific electrocardiographic (ECG) changes have been reported, as well as various supraventricular and ventricular tachycardias, in patients with pheochromocytoma.

In the very rare situation in which a strong discordance is noted between symptoms and laboratory findings, one must consider the possibility of factitious administration of catecholamines. In this rare situation, as in other cases of factitious illness, an association of the individual with someone in the medical profession appears to be one of the common elements and should raise appropriate suspicion.

Patterns of biochemical test results that are more suggestive of sympathoadrenomedullary activation than of a tumor (e.g., as occurs in hypernoradrenergic hypertension, renovascular hypertension, congestive heart failure, panic disorder, and dumping syndrome) include proportionally larger elevations above the normal limits of plasma norepinephrine or epinephrine than of plasma normetanephrine or metanephrine.

Although severe paroxysmal hypertension should always raise suspicion of pheochromocytoma, it can also reflect a clinical entity called pseudopheochromocytoma. Pseudopheochromocytoma refers to the large majority of individuals (often women) with severe paroxysmal hypertension, whether normotensive or hypertensive between episodes, in whom pheochromocytoma has been ruled out.76,77 Recent evidence indicates that pseudopheochromocytoma is a heterogeneous clinical condition subdivided into a primary and a secondary form. In contrast to a primary form, a secondary form is associated with various pathologies (e.g., hypoglycemia, autonomic epilepsy, baroreceptor failure) and medications, or with drug abuse.

The most common clinical characteristics of this syndrome might be attributable in many cases to short-term activation of the sympathetic nervous system. Paroxysmal hypertension usually is associated with tachycardia, palpitations, nervousness, tremor, weakness, excessive sweating, pounding headache, feeling hot, and facial paleness or (rarely) redness. In contrast to pheochromocytoma, patients with pseudopheochromocytoma more often present with panic attacks or anxiety, flushing, nausea, and polyuria.76–78 All these symptoms well resemble a syndrome described by Page.⁷⁹ Equally interesting were his observations that “an attack is brought on by excitement” and that the syndrome has a clear predominance in women. Among the important features distinctive from pheochromocytoma are the circumstances under which episodes occur. In pseudopheochromocytoma, symptoms may be provoked rarely by some identifiable event. It is important, therefore, in questioning these patients, to search for specific provocative factors that may have precipitated these episodes. Similar to pheochromocytoma, episodes may last from a few minutes to several hours and may occur daily or once every few months. Between episodes, blood pressure is normal or may be mildly elevated. Pseudopheochromocytoma is sometimes treatable by antihypertensive drugs or psychotherapy.

Multiple Endocrine Neoplasia Syndromes

MEN2 is an autosomal dominantly inherited syndrome (Sipple’s syndrome) that consists of pheochromocytoma, medullary carcinoma of the thyroid, and hyperparathyroidism.94–96 It affects about 1 in 40,000 individuals and is characterized by medullary thyroid carcinoma, pheochromocytoma, and parathyroid hyperplasia/adenoma.⁹⁷

The gene responsible for MEN2 is a proto-oncogene called RET.⁹⁸ In contrast to MEN1, RET is specifically expressed in neural crest–derived cells such as calcitonin-producing C cells in the thyroid gland and catecholamine-producing chromaffin cells in the adrenal gland. Whether it is also expressed in the parathyroid glands remains to be ascertained, especially when the low rate of hyperparathyroidism in patients with MEN2A and the lack of hyperparathyroidism in those with MEN2B are considered, although both conditions are caused by mutations in the RET gene. RET plays a role in normal gastrointestinal neuronal and kidney development, as exemplified by the RET knockout mouse, which has a Hirschsprung-like phenotype and renal cyst or agenesis.⁹⁹ RET is located on chromosome 10q11.2 and encodes a receptor tyrosine kinase, RET protein. As an oncogene, activation of RET leads to hyperplasia of target cells in vivo. Subsequent secondary events then lead to tumor formation.¹⁰⁰ RET consists of 21 exons with 6 so-called “hot spot exons” (exons 10, 11, 13, 14, 15, and 16) in which mutations are identified in 97% of patients with MEN2. Recently, it has been proposed that in addition to other events, RET protein accumulation, secondary to absent or reduced VHL protein, may then cause transformation of selected chromaffin cells to pheochromocytoma.¹⁰⁰ Additional studies are needed to clarify whether such somatic VHL gene alterations in MEN2-associated tumors play a role in early or late tumorigenesis or rather in tumor progression. RET germline mutation screening is commercially available (in the US, http://endocrine.mdacc.tmc.edu; Mayo Clinic, Rochester, MN) and has widely replaced the cumbersome provocative testing of calcitonin stimulation (with calcium and/or pentagastrin), which has been unreliable.

Pheochromocytomas (at least 70% of which are bilateral) develop on a background of adrenomedullary hyperplasia and become manifest (e.g., biochemically or on imaging) in about 50% of patients. MEN2-associated pheochromocytomas are almost exclusively benign (with <5% reported to be malignant) and localized to the adrenals. The peak age is around 40 years, but children as young as 10 years can be affected.101,102

Patients with MEN2-related pheochromocytoma often lack sustained hypertension or other symptoms (they occur only in about 50%). Because MEN-related pheochromocytomas secrete epinephrine, stimulation of β-adrenergic receptors causes palpitations and tachycardia. Therefore, their detection is based mainly on elevated plasma metanephrine and epinephrine levels. In patients with pheochromocytomas that exclusively produce normetanephrine, MEN2 can be excluded. MEN2-related pheochromocytomas are almost always intra-adrenal, are often bilateral (≈30% at diagnosis), and are rarely malignant (<5%).46,103 In addition, as with most epinephrine-secreting pheochromocytomas, the hypertension is more likely to be paroxysmal than sustained. For these reasons, the diagnosis is easy to miss.

Medullary thyroid carcinoma is found in most patients with MEN2A, pheochromocytoma in a somewhat lesser percentage, and hyperparathyroidism in only about 25% of affected patients. Pheochromocytomas in MEN 2A most often are diagnosed at between 30 and 40 years of age. The syndrome results from germline mutations in the RET proto-oncogene on chromosome 10 (10q11.2).⁹⁸

Patients with MEN2B have pheochromocytoma, medullary carcinoma of the thyroid, ganglioneuromatosis, multiple mucosal neuromas of eyelids, lips, and tongue, and some connective tissue disorders that include marfanoid habitus, scoliosis, kyphosis, pectus excavatum, slipped femoral epiphysis, and pes cavus.¹⁰⁴ This syndrome also appears to be caused by germline mutations in the RET proto-oncogene on chromosome 10, but these mutations affect the tyrosine kinase catalytic site of the protein.¹⁰⁵ In children with MEN2B-associated pheochromocytomas, a higher risk of malignancy compared with MEN2A or sporadic disease is found.¹⁰⁶

MEN1 (Wermer’s syndrome) consists of hyperparathyroidism, pituitary adenomas, and pancreatic islet cell tumors. Pheochromocytoma is not usually part of this complex; however, the occurrence of pheochromocytoma and pancreatic islet cell tumors has been reported in some families.¹⁰⁷ Often, the islet cell tumors are nonfunctional. Various “crossover” syndromes have been reported in which pheochromocytoma has been associated with characteristics of MEN1, MEN2A, MEN2B, von Recklinghausen’s neurofibromatosis (NF), VHL, and the Zollinger-Ellison syndrome.¹⁰⁸ It has been proposed that the combination of neurofibromatosis, duodenal carcinoid, and pheochromocytoma constitutes a neuroendocrine syndrome that is separate from the combination of VHL, islet cell tumor, and pheochromocytoma.¹⁰⁹

Von Hippel-Lindau Syndrome

Another neuroectodermal syndrome commonly associated with pheochromocytoma is VHL syndrome, which is caused by mutations in chromosome 3 (3p25-26), which encodes the VHL tumor suppressor gene.¹¹⁰ Pheochromocytomas in VHL disease typically develop according to Knudson’s two-hit model, including an inherited germline mutation of VHL and loss of function of the wild-type allele of the VHL gene. The disease has been divided into two types based on the significant genotype-phenotype correlations observed. Type 1 includes mainly large deletions or mutations and expresses the full phenotype of vascular lesions of the retina, cysts or solid tumors in the brain or spinal cord, pancreatic cysts, renal cell carcinoma, epididymal cystadenoma, and endolymphatic sac tumors, but no pheochromocytoma. Type 2 has missense mutations, pheochromocytoma, and the full phenotype.¹¹¹ Patients often are asymptomatic when they present with other aspects of this disease. This syndrome is variable in terms of the different organ systems involved and the extent of involvement from patient to patient and from family to family. Overall, less than 30% of patients with a VHL germline mutation develop a pheochromocytoma. Pheochromocytomas as part of the VHL syndrome have an exclusively noradrenergic phenotype, reflecting the production of norepinephrine only.¹¹² These tumors are located mainly intra-adrenally and are bilateral in about 50% of patients, with a less than 7% incidence of metastases. Because they do not express glucagon receptors, the glucagon test should not be used for detection of these tumors. These tumors are commonly found on the basis of periodic annual screening, or during searches for other tumors that are part of this syndrome. Therefore, when detected, these tumors are commonly small; they often fail to be detected by nuclear imaging methods. Furthermore, about 80% of pheochromocytomas found in patients with VHL during screening are asymptomatic and are not associated with hypertension.

Neurofibromatosis Type 1

Von Recklinghausen’s NF is now divided into two types: NF-1 has neurofibromas of peripheral nerves, whereas NF-2 has central neurofibromas. NF-1 is inherited in an autosomal dominant pattern. The association with pheochromocytoma is one between a relatively common disease and a rare disease. Thus, although less than 1% to 2% of patients with NF have pheochromocytoma, about 5% of patients with pheochromocytoma have NF.¹¹³ Pheochromocytoma associated with NF-1 is caused by germline mutations in chromosome 17 (17q11), where the NF-1 gene encodes for the protein neurofibromin. These mutations lead to inactivation of this tumor suppressor gene and its protein.¹¹⁴ Similar mutations introduced into the NF-1 gene in mice lead to pheochromocytoma, which is otherwise rare in these animals.¹¹⁵ Pheochromocytoma in patients with NF-1 is rarely seen in children, because it usually occurs at a later age (around 50 years). Only 12% of patients with NF-1 are diagnosed with bilateral and multifocal pheochromocytomas, and less than 6% of patients have metastatic pheochromocytoma.¹¹⁶

The incidence of pheochromocytoma in NF-1 is relatively low (about 1%) compared with other hereditary syndromes, and routine screening of such patients generally is not recommended. However, if a patient with NF-1 has hypertension, then a pheochromocytoma should be considered and excluded.¹¹³

Succinate Dehydrogenase Gene Family

Recently, pheochromocytoma susceptibility has been associated with germline mutations of the succinate dehydrogenase (SDH) gene family.117,118 The SDH genes (SDHA, SDHB, SDHC, and SDHD) encode the four subunits of complex II of the mitochondrial electron transport chain,¹¹⁹ which is essential for the generation of ATP (oxidative phosphorylation). SDHB and SDHD mutations can lead to complete loss of SDH enzymatic activity, a phenomenon that has been linked to tumorigenesis through upregulation of hypoxic-angiogenetic responsive genes.¹²⁰ Unlike the SDHA gene, mutations of SDHB, SDHC, and SDHD genes are associated with the presence of familial and nonfamilial pheochromocytoma and parasympathetic paraganglioma. Frameshift, missense, and nonsense mutations were identified for the SDH gene family. In recent studies, it has been found that about 4% to 12% of sporadic pheochromocytomas^12,121 and up to 50% of familial pheochromocytomas¹²¹ have SDHD or SDHB mutations. The SDHB, SDHC, and SDHD traits are inherited in an autosomal dominant fashion and give rise to familial paraganglioma (PGL) syndromes 4, 3, and 1, respectively (see Table 14-4). The penetrance of these traits is incomplete, however. Furthermore, SDHD-related disease is characterized by maternal genomic imprinting. Because of silencing of the maternal allele by methylation, individuals who inherit a mutation from their mother remain free of paraganglioma but still may pass on the mutation to their offspring. SDHB mutations predispose to mainly extra-adrenal pheochromocytomas with a high malignant potential, and less frequently to benign parasympathetic head and neck paragangliomas.^62,122–124 SDHD mutations typically are associated with multifocal parasympathetic head and neck paragangliomas and usually with benign extra-adrenal and adrenal pheochromocytomas.^122,124 Metastastic pheochromocytoma is rare in SDHD mutation carriers, but it can occur.^123,125 SDHC mutations are rare and are almost exclusively associated with parasympathetic head and neck paraganglioma,¹²⁶ although rare cases of SDHC-associated extra-adrenal pheochromocytoma have been reported.^127,128 Most SDHB-related paragangliomas secrete norepinephrine or both norepinephrine and dopamine,⁶² a profile that is consistent with mainly extra-adrenal tumors. Some SDHB-related PGLs exclusively overproduce dopamine, but not other catecholamines ^62,129–131 Therefore, measurement of plasma levels of dopamine or its O-methylated metabolite methoxytyramine should be considered in SDHB-related pheochromocytoma. As mentioned, ≈10% of SDHB-related sympathetic paragangliomas are “biochemically silent.” The biochemical phenotype of SDHD-associated pheochromocytoma has not been studied consistently.

We recommend to offer genetic testing, preceded by careful genetic counseling, to all first-degree family members of patients with SDH-related pheochromocytoma and paraganglioma,¹³² and to subsequently carry out a periodic clinical, biochemical, and radiologic tumor screening among mutation carriers, especially those with an SDHB mutation. No evidence-based protocol has been used for tumor screening among children with a known SDHB, or any other mutation. We recommend periodic biochemical and total body magnetic resonance imaging (MRI) screening from as early as age 7.

Sporadic and Other Pheochromocytomas

Genetic analyses of DNA from sporadic pheochromocytoma have yielded variable results, with up to 20% RET mutations (half MEN2A and half MEN2B) in some series, and up to 20% VHL mutations in others.46,133,134 In another study, 45% of sporadic adrenal pheochromocytomas had loss of heterozygosity at the VHL gene locus, but no genetic abnormalities were found in sporadic extra-adrenal pheochromocytomas.¹³⁵ Genetic analysis provides positive identification of carriers in familial syndromes and thus identifies who should be screened and who need not be screened for the various traits of the phenotype.

Pheochromocytoma also may occur as part of Carney’s triad (i.e., gastric leiomyosarcoma, pulmonary chondroma, and extra-adrenal pheochromocytoma).¹³⁶ The syndrome is very rare; fewer than 30 cases have been reported, and only 25% of patients manifest all three parts of the triad. It occurs sporadically and is clearly nonfamilial.¹³⁷ Recently, a new syndrome called the Stratakis-Carney syndrome, or the “dyad of gastrointestinal stromal tumor and paraganglioma” associated with SDHB, SDHC, and SDHD mutations, was identified.¹³⁸

For the genetic diagnosis of pheochromocytoma, a panel of experts at the International Symposium on Pheochromocytoma 2005 held in Bethesda, Maryland, agreed that, although there is now a reasonable argument for more widespread genetic testing, it is neither appropriate nor currently cost-effective to test for every disease-causing gene in every patient with a pheochromocytoma or paraganglioma. Rather, it was stressed that the decision to test, and which genes to test, requires judicious consideration of numerous factors, several of which are noted in Fig. 14-6.

Initial Biochemical Testing

Missing a pheochromocytoma can have deadly consequences. Therefore, one of the most important considerations in the choice of an initial biochemical test is a high level of reliability that the test will provide a positive result in that rare patient with the tumor. Such a test also provides confidence that a negative result reliably excludes the tumor, thereby avoiding the need for multiple or repeat biochemical tests or even costly and unnecessary imaging studies to rule out the tumor. Therefore, the initial workup of a patient with suspected pheochromocytoma should include a suitably sensitive biochemical test.

Catecholamine secretion by pheochromocytomas can be episodic or, in patients who are asymptomatic, negligible in nature. Thus, measurements of urinary or plasma catecholamines do not provide reliable biochemical tests for detection of the tumor. This is particularly problematic during screening for pheochromocytoma in patients with a predisposing hereditary condition, where 26% to 29% of tumors can be expected to be associated with normal urinary excretion or plasma concentrations of catecholamines.¹³⁹ Because of the intermittent nature of catecholamine secretion, it has been recommended that urine or blood samples are best collected when the patient is hypertensive. Hypertension, however, can be present in some patients independently of catecholamine release by a tumor. Thus, normal catecholamines in a patient with hypertension do not exclude pheochromocytoma.

Because metanephrines are produced continuously within pheochromocytoma tumor cells, and independently of catecholamine release, these measurements obviate any need for collection of blood or urine samples during hypertensive episodes. This understanding has provided a rationale for subsequent studies examining the utility of measurements of plasma free metanephrines for diagnosis of pheochromocytoma.8,9,139–144 At the National Institutes of Health (NIH), the superiority of plasma free metanephrines over other tests was established in a series of three published reports,^9,139,143 culminating in a study involving more than 850 patients, including 214 with pheochromocytoma.⁹ Plasma free metanephrines showed superior combined diagnostic sensitivity and specificity over all other tests examined, including urinary and plasma catecholamines, urinary vanillylmandelic acid, and urinary total and fractionated metanephrines. Analysis of receiver-operating characteristic curves showed that at equivalent levels of sensitivity, the specificity of plasma free metanephrines was higher than that of all other tests, and that, at equivalent levels of specificity, the sensitivity of plasma free metanephrines was also higher than that of all other tests, even when the latter were combined.

The high diagnostic sensitivity of measurements of plasma free metanephrines has now been independently confirmed by four other groups of investigators.8,140,142 All together, the five independent studies—with 336 patients with pheochromocytoma and close to 2500 patients in whom the tumor was excluded—have indicated an overall diagnostic sensitivity of 98% and specificity of 92% for measurement of plasma free metanephrines.

Metanephrines in urine usually are measured after a deconjugation step that liberates free metanephrines from sulfate- or glucuronide-conjugated metanephrines,145,146 whereas plasma metanephrines are measured most often in the free form, but they can also be measured after a deconjugation step (Fig. 14-7). Conjugated metanephrines are present in urine and plasma at much higher concentrations than are free metanephrines. Adding to the confusion in terminology is the fact that historically metanephrines were measured in urine by spectrophotometric methods as “total” metanephrines, representing the combined sum of deconjugated normetanephrine (the O-methylated metabolite of norepinephrine) and deconjugated metanephrine (the O-methylated metabolite of epinephrine).

Spectrophotometric measurements of total metanephrines have been largely phased out in favor of newer chromatographic methods that allow fractionated measurements of normetanephrine and metanephrine (hence the term fractionated metanephrines). Reports of “fractionated” metanephrines still often include a value for “total” metanephrines as a holdover from earlier spectrophotometic measurements, but this vestigial line in the report offers little value to the clinician. Because many pheochromocytomas produce mainly (or solely) only one of the two metabolites, separate measurements of normetanephrine and metanephrine ensure that small or mild increases in one metabolite are not diluted by normal levels of the other. Separate measurements also allow distinction of norepinephrine from epinephrine-producing pheochromocytomas, which as discussed later can provide additional useful information about a possible pheochromocytoma.

Sampling Procedures and Interferences

The conditions under which blood or urine samples are collected can be crucial to the reliability and interpretation of test results. Blood for measurements of plasma-free metanephrines or catecholamines ideally should be collected with patients supine for at least 20 minutes before sampling.¹⁴⁷ To avoid any stress associated with the needlestick, samples ideally should be collected through a previously inserted IV. Alternatively, the sample may be taken by needlestick from a seated patient, provided that upper reference limits obtained after supine rest using an indwelling IV are used.¹⁴⁸ False positives in this situation are more prevalent. Thus, if the seated test returns a positive result, sampling should be repeated after rest in the supine position to rule out a false-positive initial test. Patients should have refrained from nicotine and alcohol for at least 12 hours and, to minimize analytic interference, should have fasted overnight before blood sampling.

A 24-hour collection of urine is often favored over blood sampling, because this avoids the rigid sampling conditions associated with blood collection and is more convenient for clinical staff to implement. However, 24-hour collections of urine are not always easily, conveniently, or reliably collected by patients, particularly pediatric patients. Also, the influences of diet and of sympathoneuronal and adrenal medullary systems activation (associated with physical activity or changes in posture) are not controlled as easily as they are for blood collections. Thus, some investigators advocate spot or overnight urine collections with output of catecholamines or metanephrines normalized against urinary creatinine excretion.¹⁴⁹ Additional considerations for urine collected under these conditions include dietary protein, muscle mass, level of physical activity, and time of day, all of which influence creatinine excretion and confound interpretation of results.

Dietary constituents or medications can cause direct analytic interference in measurements of catecholamines and metabolite levels or may influence the physiologic processes that determine these levels. Analytic interference can be highly variable, depending on the particular measurement method used, whereas physiologic interference is usually of a more general nature and is independent of the measurement method used (Table 14-5). Tricyclic antidepressants, in particular, are a major source of physiologic interference.¹⁵⁰ The high incidence of false-positive results for plasma or urinary norepinephrine and normetanephrine in patients taking tricyclics is presumably caused by the primary inhibitory actions of these agents on monoamine reuptake. The result is an increased escape of norepinephrine from sympathetic nerve terminals into the bloodstream.

The development of new drugs, variations in assay techniques, and continuing improvements in analytic procedures make it difficult to identify which directly interfering medications should be avoided for a given analytic test. Labetalol and its metabolites, which were common sources of analytic interference with spectrometric and fluorometric measurements of catecholamines and metanephrines, now represent only a variable source of interference for high-pressure liquid chromatographic (HPLC) measurements of catecholamines, with interference mainly affecting epinephrine determinations.¹⁵¹ The anxiolytic agent buspirone (Buspar) is another drug that can cause falsely elevated levels of urinary metanephrine in some but not all HPLC assays of urinary fractionated metanephrines.¹⁵⁰ Similarly, acetaminophen can directly interfere with measurements of normetanephrine in some HPLC assays, but not in others.^152,153

Biochemical Algorithm

Expert recommendations for initial biochemical testing from the International Symposium on Pheochromocytoma include measurements of fractionated metanephrines in urine or plasma, or both, as available.154,156 No consensus was reached on whether plasma or urine measurement should be the preferred test. Both tests offer similarly high diagnostic sensitivity (provided appropriate reference ranges are used), so that a negative result for either test appears equally effective for excluding pheochromocytoma. However, because of differences in specificity, tests of plasma free metanephrines exclude pheochromocytoma in more patients without the tumor than do tests of urinary fractionated metanephrines. Additional measurements of urinary or plasma catecholamines may be carried out, but in our experience are unlikely to lead to detection of additional tumors not indicated by elevated levels of normetanephrine or metanephrine. Exceptions include rare tumors that produce exclusively dopamine.⁸ With a mind to the above exception, the decision to rule out pheochromocytoma should be based primarily on findings of negative test results for measurements of normetanephrine and metanephrine. An algorithm for the biochemical diagnosis of pheochromocytoma is given in Fig. 14-8.

Follow-Up Biochemical Testing

Follow-up biochemical testing usually should be necessary only in patients with positive results of initial tests of plasma free or urinary fractionated metanephrines. Exceptions include patients at high risk for pheochromocytoma because of a hereditary syndrome or a prior history of the tumor, all of whom should undergo periodic screening. In these patients, and occasionally in others with adrenal incidentalomas, the tumors may be too small to produce signs and symptoms or a positive result by any available biochemical test. In these patients, positive results likely will follow enlargement of tumors.

Because of the large numbers of patients tested for pheochromocytoma and the rarity of the tumor, false-positive results can be expected to outnumber true-positive results, even for tests with reasonably high specificity. Thus, the likelihood of pheochromocytoma in a patient with a positive result is usually low. Follow-up tests are invariably required to unequivocally confirm or exclude the tumor, the extent and nature of this requiring informed and sound clinical decision making. Thus, the clinician who judges the likelihood of a pheochromocytoma from a single positive test result should first take into account the degree of initial clinical suspicion or pretest probability of the tumor, which affects the posttest probability of a tumor.

The extent of the increase in a positive test result is crucially important for judging the likelihood of a pheochromocytoma. Most patients with the tumor have increases in plasma or urinary metanephrines well in excess of those more commonly encountered as false-positive results in patients without the tumor. Increases in plasma concentrations of normetanephrine to above 400 ng/L (2.2 nmol/L) or of metanephrine to above 236 ng/L (1.2 nmol/L) are extremely rare in patients without pheochromocytoma, but occur in about 80% of patients with the tumor.⁹ Similarly, increases in urinary output of normetanephrine to above 1500 µg/day (8.2 µmol/day) or of metanephrine to above 600 µg/day (3.0 µmol/day) are rare in patients without pheochromocytoma, but occur in about 70% of patients with the tumor. Provided that biochemical test results are accurate, the likelihood of pheochromocytoma in such a patient is so high that the immediate task is to locate the tumor.

When concern is expressed about the analytic accuracy of a positive plasma test result, this can be checked by a follow-up urinary test, and vice versa concern arises about an initial urinary test result. Such follow-up testing may be particularly prudent in patients with milder increases in plasma free or urinary fractionated metanephrines, where the posttest probability of pheochromocytoma remains low, and where subtle analytic interferences can be difficult for the testing laboratory to recognize. A similar pattern of increases in urinary and plasma normetanephrine or metanephrine not only helps confirm the accuracy of results but increases the likelihood of a pheochromocytoma.

Before follow-up testing is implemented, some consideration should be given to sources of false-positive results, including accompanying medical conditions, inappropriate sampling conditions, dietary influences, and medications likely to directly interfere with analytic results or to increase levels of normetanephrine or metanephrine (see Table 14-5). Among the latter, tricyclic antidepressants and phenoxybenzamine (Dibenzyline) can be common sources of false-positive results.¹⁵⁰ Tricyclic antidepressants elevate plasma and urinary norepinephrine and normetanephrine through blockade of norepinephrine reuptake at sympathetic nerve endings, and these are contraindicated in patients with pheochromocytoma. Phenoxybenzamine also increases plasma and urinary norepinephrine and normetanephrine, presumably by blocking presynaptic α₂-adrenoceptors and releasing sympathetic nerves from the inhibitory effects of occupation of these receptors on norepinephrine release. Therefore, phenoxybenzamine should not be used for treatment until biochemical testing is complete and confirms the presence of tumor.

Additional sampling for plasma catecholamines, in combination with plasma free metanephrines or urinary catecholamines, in combination with urinary fractionated metanephrines, can provide further useful information to help distinguish true-positive from false-positive results.¹⁵⁰ Because free metanephrines are produced continuously within pheochromocytoma tumor cells by a process that is independent of catecholamine release, patients with true-positive results usually have larger percent increases in plasma metanephrines to above the upper reference limits than percent increases in the parent catecholamines. Conversely, because substantial amounts of metanephrine (greater than 90%) and normetanephrine (26% to 40%) are normally produced within adrenal medullary cells, independently of catecholamine release, increases in metanephrines during activation of sympathoneuronal and adrenal medullary systems are smaller than increases in catecholamines. Thus, patients with false-positive results caused by sympathoneuronal and adrenal medullary systems activation usually have larger percent increases in plasma norepinephrine than in plasma normetanephrine or plasma epinephrine than in metanephrine.

Because of relatively poor diagnostic sensitivity, measurements of urinary VMA or of urinary “total” metanephrines are of limited value for detecting or excluding pheochromocytoma. Such tests rarely provide useful diagnostic information beyond that attained by measurement of plasma or urinary fractionated metanephrines, where normetanephrine and metanephrine are measured separately. Exceptions include metastases confined to the liver or to mesenteric organs where the vascular drainage from tumors enters the liver, the main site in the body for formation of VMA from catecholamines and catecholamine metabolites.

Pharmacologic Tests

Various pharmacologic tests have been used over the years in an attempt to improve diagnostic accuracy for pheochromocytoma. This was especially true years ago, when the assays for catecholamines and their metabolites were new, crude, and often undependable. However, provocative tests are inherently dangerous, as indicated by the several deaths that have been reported during histamine testing.¹⁵⁷ In light of the much improved quality of present assays, the use of these pharmacologic procedures has been greatly reduced. On the other hand, suppression tests may be useful and bear lower risk.

Clonidine (Catapres) is now the drug used most often in suppression tests to identify a pheochromocytoma.48,158 It is a centrally acting α₂-adrenergic agonist that suppresses central sympathetic nervous outflow; this normally results in lower levels of plasma catecholamines. Blood is drawn for plasma catecholamines before and 3 hours after the oral administration of clonidine 0.3 mg/70 kg body weight. Tricyclic antidepressants and diuretics are reported to compromise reliability of the test¹⁵⁹; therefore, these medications should be withdrawn before testing is begun. Profound hypotensive responses to clonidine can be troublesome in some patients taking antihypertensive medications; therefore, these should be stopped on the day of the test. Plasma catecholamine levels will decrease if they are under normal physiologic control, whereas in patients with pheochromocytoma, plasma catecholamines will not decrease.

The clonidine suppression test is unreliable in patients with normal or only mildly increased plasma catecholamine levels.¹⁶⁰ In such patients, normal suppression of plasma norepinephrine may occur after administration of clonidine despite the presence of a pheochromocytoma. Presumably, normal suppression occurs because much of the norepinephrine is derived from sympathetic nerves and remains responsive to clonidine. The clonidine suppression test therefore is recommended for patients with plasma catecholamine levels over 5.9 nmol/L (1000 pg/mL), with a normal response defined as a fall to within the normal range.¹⁵⁸ This recommendation makes it problematic to use the test in patients with normal or only mildly elevated plasma catecholamine levels, which is particularly troublesome because such patients represent those in whom it is most difficult to conclusively diagnose pheochromocytoma.

Additional measurements of plasma normetanephrine before and after clonidine provide a method for overcoming the above limitation in patients with elevated plasma concentrations of normetanephrine, but normal or mildly elevated plasma concentrations of norepinephrine.¹⁵⁰ A decrease in plasma levels of normetanephrine of more than 40% or to below the upper reference limit (0.61 nmol/L = 112 pg/mL) was present in all patients without pheochromocytoma, indicating a diagnostic specificity of 100%. This was similar to that for norepinephrine (specificity = 98%), where pheochromocytoma could be excluded by a decrease in norepinephrine of more than 50% or a level of norepinephrine after clonidine below 2.94 nmol/L (498 pg/mL). Among patients with pheochromocytoma, only 2 of 48 had plasma levels of normetanephrine that fell by more than 40% or to below 0.61 nmol/L (112 pg/mL) after clonidine. This indicated a diagnostic sensitivity for normetanephrine responses to clonidine of 98%, which represents a substantial improvement over the sensitivity of only 67% for norepinephrine responses. Thus, the clonidine suppression test, combined with measurements of plasma normetanephrine, provides an efficient and reasonably reliable method for distinguishing false-positive from true-positive elevations in plasma normetanephrine.

As was noted previously, provocative tests are inherently dangerous and are rarely called for. Glucagon is the drug that is usually used.75,161 A positive test result is usually defined as an increase in plasma norepinephrine of greater than threefold or to more than 2000 pg/mL, 2 minutes after an IV bolus of 1.0 mg.¹⁶² The test has high diagnostic specificity but limited sensitivity. Phentolamine must always be at hand for the treatment of any episodes of severe hypertension.

Additional Interpretative Considerations

Pheochromocytomas differ considerably in rates of catecholamine synthesis, turnover, and release, and in the types of catecholamines and metabolites produced. These differences may explain variations in presenting signs and symptoms; they also can provide useful information about the tumor, including the adrenal or extra-adrenal location, the underlying mutation, tumor size, and the presence of metastatic disease.

Adrenal pheochromocytomas may produce near exclusively norepinephrine, or both norepinephrine and epinephrine. In contrast, extra-adrenal pheochromocytomas almost invariably produce exclusively norepinephrine.³⁶ Differences in plasma concentrations or urinary outputs of normetanephrine and metanephrine reflect underlying differences in tumor catecholamine phenotype better than do differences in plasma or urinary norepinephrine and epinephrine. Thus, patients with increases in only normetanephrine may have tumors with an adrenal or extra-adrenal location, whereas those with additional or exclusive increases in metanephrine are likely to have a tumor with an adrenal location. Exceptions to the above rule have been described in patients with recurrence or spread from a primary epinephrine-producing tumor with an adrenal location.¹⁶³

Pheochromocytomas that produce mainly epinephrine (and hence also produce large amounts of metanephrine) tend to present more often with alternating hypertension and hypotension and to be more paroxysmal in nature than do those that produce exclusively norepinephrine.164,165 Patients with tumors that secrete large amounts of epinephrine may present with signs and symptoms that reflect the potent actions of epinephrine on glucose metabolism and pulmonary physiology (e.g., hyperglycemia, dyspnea, pulmonary edema).^59,166 Among patients with hereditary pheochromocytoma, differences in metanephrine production distinguish MEN2 from VHL, and can provide a supplementary guide to clinical presentation for deciding which gene to test to unambiguously identify the underlying germline mutation.¹⁶⁷

Mutation-dependent differences in expression of genes may explain the progression from benign to malignant pheochromocytoma, which often is characterized by a dedifferentiated state. Norepinephrine is usually the predominant catecholamine produced.168,169 Metastatic pheochromocytomas sometimes can be characterized by high tissue, plasma, and urinary levels of dopa and dopamine, the immediate precursors of norepinephrine.^169–171 Elevations in plasma or urinary dopa and dopamine are not in themselves particularly sensitive or specific markers of benign or metastatic pheochromocytoma. However, when accompanied by elevations in plasma norepinephrine or other clinical evidence of pheochromocytoma, such elevations should arouse immediate suspicion of metastatic disease.

A consequence of the considerable variation in catecholamine release noted among patients with pheochromocytoma is that plasma concentrations or urinary excretion of catecholamines is poorly correlated with tumor size.⁴⁴ In contrast, because of metabolism of catecholamines within tumors and the independence of this process on catecholamine release, urinary excretion or plasma concentrations of metanephrines show strong positive correlation with tumor size and can be useful for judging the extent and progression of disease.^139,172

Anatomic Imaging

In most institutions, computed tomography (CT) of the abdomen, with or without contrast, provides the initial method of localizing pheochromocytoma because this imaging technique is easy, widely available, and relatively inexpensive. CT can be used to localize adrenal tumors 1 cm or larger and extra-adrenal tumors 2 cm or larger (sensitivity is about 95%, but specificity is only about 70%).¹⁷⁸ Administration of intravenous contrast media for CT scanning is preferred, but these agents have been suggested to evoke catecholamine release from tumors. However, a study in which the nonionic contrast medium iohexol was used did not find any support for this notion.¹⁷⁹ In our experience, intravenous contrast does not elicit increases in plasma catecholamines, blood pressure, or heart rate.

A homogeneous mass with a density measurement of less than 10 HU on unenhanced CT is most probably a nonfunctioning benign adenoma, as opposed to most pheochromocytomas, which usually exhibit a density of more than 10 HU and an inhomogeneous appearance. The disadvantage of CT is that it may fail to localize recurrent pheochromocytomas because of postoperative anatomic changes and the presence of surgical clips. Because extra-adrenal pheochromocytomas are located most commonly in the abdomen, we suggest that CT of the abdomen, including the pelvis, be done first. This should be followed by chest and neck imaging if abdominal CT is negative.

MRI with or without gadolinium enhancement is also a very reliable method of detection and may identify more than 95% of tumors; it is superior to CT in detecting extra-adrenal tumors.¹⁸⁰ On MRI T1 sequences, pheochromocytoma has a signal similar to that of liver, kidney, and muscle, and can be differentiated with ease from adipose tissue. Chemical shift MRI characterizes adrenal masses on the basis of the presence of fat in benign adenomas and the absence of fat in pheochromocytoma, metastases, hemorrhagic pseudocysts, or malignant tumors. The hypervascularity of pheochromocytoma makes them appear characteristically bright, with a high signal on T2 sequence and no signal loss on opposed-phase images. More particularly, almost all pheochromocytomas have a more intense signal than that of the liver or muscle and often more intense than fat on T2-weighted images. However, such intense signals can be elicited by hemorrhage or hematomas, adenomas, and carcinomas, so an overlap with pheochromocytoma must be considered, and specific additional imaging is needed to confirm that the tumor is pheochromocytoma.¹⁸¹ Atypical pheochromocytomas may show medium signal quality on T2-weighted images and an inhomogeneous appearance, especially if they are cystic.

Among the advantages of MRI imaging of pheochromocytoma are its high sensitivity in detecting adrenal disease (93% to 100%) and the lack of exposure to ionizing radiation.¹⁸² MRI is a good imaging modality for the detection of intracardiac, juxtacardiac, and juxtavascular pheochromocytomas because it reduces cardiac and respiratory motion-induced artifacts, whereas the use of T2 sequences enables better differentiation from surrounding tissues. MRI offers the possibility of multiplanar imaging and of superior assessment of the relationship between a tumor and its surrounding vessels (the great vessels in particular) compared with CT, rendering this modality of utmost importance in the evaluation of patients with pheochromocytoma in these areas, and especially to rule out vessel invasion. However, its overall sensitivity for detection of extra-adrenal, metastatic, or recurrent pheochromocytoma is lower compared with that of adrenal disease (90%). Overall, the specificity of MRI is about 70%.¹⁷⁸ MRI should be used as the initial imaging procedure when there is pregnancy or allergy to the contrast materials used for CT scans. However, MRI is more expensive than CT. Currently, no consensus indicates whether CT or MRI is preferred for initial localization of a tumor. Anatomic imaging should focus initially on the abdomen and pelvis.¹⁵⁴ We do not recommend ultrasound to localize pheochromocytoma: exceptions to this rule include children and pregnant women when MRI is not available.

Functional Imaging

Functional imaging studies (enabled by the presence of the cell membrane and vesicular catecholamine transport systems in pheochromocytoma cells) include ¹²³I- or ¹³¹I-MIBG scintigraphy, 6-¹⁸F-fluorodopamine, ¹⁸F-dihydroxyphenylalanine (¹⁸F-dopa), ¹¹C-hydroxyephedrine, and ¹¹C-epinephrine positron emission tomography (PET).6,7,163,183–185 These modalities can be used to confirm that a tumor is a pheochromocytoma and can detect most cases of metastatic disease.

However, it should be noted that malignant pheochromocytoma may undergo tumor dedifferentiation with loss of specific neurotransmitter transporters, leading to an inability to accumulate these isotopes and consequent lack of localization. ¹⁸F-fluoro-deoxyglucose (FDG)-PET scanning or somatostatin receptor scintigraphy may be required as the only next step of the imaging algorithm. FDG is a nonspecific imaging agent whose accumulation is based on the higher metabolic rate of tumors compared with surrounding normal tissue. Another characteristic of dedifferentiated tumors involves the loss or the gain of specific receptors. More particularly, malignant pheochromocytomas often express somatostatin receptors,¹⁸⁶ thus enabling somatostatin receptor scintigraphy with the somatostatin analogue octreotide (Octreoscan).

Metaiodobenzylguanidine Scintigraphy

In rare cases, pheochromocytoma cannot be localized by CT or MRI studies. This may be caused by very small tumor size or by unusual location of a tumor (e.g., in the heart or neck). In such cases, whole body scanning using MIBG labeled with radioiodine (¹²³I or ¹³¹I) should be considered. It is capable of showing multiple lesions simultaneously, as well as showing those in unusual locations. Other tumors arising from neuroendocrine cells may also take up ¹²³I- or ¹³¹I-MIBG, and this has been reported for chemodectomas, nonsecreting paragangliomas, and carcinoids, and in both sporadic and familial medullary carcinomas of the thyroid.¹⁸⁷ MIBG yields nearly 100% specificity in detection of this tumor.¹⁸⁸

MIBG labeled with ¹³¹I provides negative results in up to 15% of patients with proven pheochromocytomas. However, much better sensitivity is available with MIBG labeled with ¹²³I.183,189 Another advantage of ¹²³I over ¹³¹I-labeled MIBG is its additional utility for imaging by single-photon emission computed tomography (SPECT). The agent also has a shorter half-life compared with ¹³¹I-MIBG (13 hours vs. 8.2 days), so that higher doses can be used.¹⁸³ The sensitivity of ¹²³I-MIBG scintigraphy is 92% to 98% for nonmetastatic pheochromocytoma,¹⁹⁰ but only 57% to 79% for metastases.^190–192 The accumulation of MIBG can be decreased by several types of drugs: (1) agents that deplete catecholamine stores, such as sympathomimetics, reserpine, and labetalol; (2) agents that inhibit cell catecholamine transporters, including cocaine and tricyclic antidepressants; and (3) other drugs such as calcium channel blockers and certain α- and β-adrenergic receptor blockers.¹⁹³ It is suggested that most of these drugs be withheld for about 2 weeks before undergoing MIBG scintigraphy. Both ¹²³I-MIBG and ¹³¹I-MIBG require saturated solution of potassium iodine (SSKI, 100 mg twice a day for 4 or 7 days, respectively) to be used to block thyroid gland accumulation of free ^123/131I. It should be noted that ^123/131I-MIBG is normally accumulated in the myocardium, spleen, liver, urinary bladder, lungs, salivary glands, large intestine, and cerebellum. Moreover, the normal adrenal gland may show MIBG uptake in as many as 75% of patients.^194,195 Some of the MIBG is taken up by platelets, and thrombocytopenia may occur.

The study is relatively expensive, and the patient usually must be scanned at 24 hours and again at 48 or 72 hours after injection of the radioisotope to determine whether images that appear on the early scan are physiologic and will fade, or are tumors and will persist or increase in intensity on the later scan.

In summary, we recommend the use of ¹²³I-MIBG rather than ¹³¹I-MIBG. ¹²³I-MIBG scintigraphy has a limited sensitivity for pheochromocytoma metastases but can be useful if ¹³¹I-MIBG therapy is anticipated. Positron emission tomography, if available, is preferred for comprehensive localization of metastatic disease.

Positron Emission Tomography

PET imaging is done within minutes or hours after injection of short-lived positron-emitting agents. Low radiation exposure and superior spatial resolution are among the advantages of PET, whereas cost and limited availability of radiopharmaceuticals and PET equipment (including cyclotron) still prohibit more widespread use.

Most PET radiopharmaceuticals used for the detection of pheochromocytoma enter the pheochromocytoma cell using the cell membrane norepinephrine transporter. Dopamine is a better substrate for the norepinephrine transporter than are most other amines, including norepinephrine. Thus, a labeled analogue of dopamine should be useful as a scintigraphic imaging agent. 6-¹⁸F-fluorodopamine, a sympathoneuronal imaging agent developed at the NIH, is a positron-emitting analogue of dopamine and was found to be a good substrate for the plasma membrane and for intracellular vesicular transporters in catecholamine-synthesizing cells.¹⁹⁶

We recently published a series of 28 patients with known pheochromocytoma in whom 6-¹⁸F-fluorodopamine-PET scans were positive and localized pheochromocytoma tumors in all.⁶ In another study,¹⁹⁷ it was shown that in patients with metastatic pheochromocytoma, 6-¹⁸F-fluorodopamine-PET localized pheochromocytomas in all patients and showed a large number of foci that were not imaged with ¹³¹I-MIBG scintigraphy (Fig. 14-9). Thus, 6-¹⁸F-fluorodopamine-PET was found to be a superior imaging method in patients with metastatic pheochromocytoma. More recently, however, we have identified several pheochromocytomas that were negative on 6-¹⁸F-fluorodopamine-PET scans (unpublished observations). All these pheochromocytomas also had negative ¹³¹I- or ¹²³I-MIBG scintigraphy.

¹¹C-hydroxyephedrine and ¹¹C-epinephrine¹⁹⁸ are other PET imaging agents that have been shown to have a limited diagnostic yield because of their less than perfect sensitivity and/or specificity. This could be caused in part by their limited affinity for cell membrane and vesicular norepinephrine transporter systems, as well as the short half-life of ¹¹C radiopharmaceuticals (20 minutes), which renders the implementation of whole-body scans difficult. ¹⁸F-fluorodopa PET has shown promising results in initial studies in a limited number of patients with pheochromocytoma.^184,199 The sensitivity of ¹⁸F-fluorodopa appears to be limited for metastases, however (unpublished observations).

Increased glucose metabolism characterizes various malignant tumors; thus the uptake of glucose labeled with ¹⁸F-fluoride can be useful in imaging these tumors. In one study of 17 patients, FDG-PET was used with some success in imaging of metastatic pheochromocytoma and revealed more metastases than ¹²³I- or ¹³¹I-MIBG scintigraphy.¹⁸⁵ Malignant pheochromocytomas may accumulate FDG more avidly than benign pheochromocytomas; nevertheless, FDG cannot distinguish malignant from benign disease. It should be noted that the use of FDG is not recommended in the initial diagnostic localization of pheochromocytoma. This radiopharmaceutical is nonspecific for this tumor. However, it can be useful in those patients in whom other imaging modalities are negative, and in rapidly growing metastatic pheochromocytoma that is becoming undifferentiated and thus losing the property to accumulate more specific agents.¹⁷³ Moreover, ¹⁸F-FDG PET is the preferred technique for localization of SDHB-associated metastatic pheochromocytoma, as previously described.¹⁹¹ Impairment of mitochondrial function due to loss of SDHB function may cause tumor cells to shift from oxidative phosphorylation to aerobic glycolysis, a phenomenon known as the “Warburg effect.”²⁰⁰ Higher glucose requirements due to a switch to less efficient pathways for cellular energy production may explain increased ¹⁸F-FDG uptake by malignant SDHB-related pheochromocytoma. This possible bioenergenetic signature on imaging awaits confirmation at a molecular level.

Overall, the advantages of PET are that it can be done within minutes or hours after injection of short-lived positron-emitting agents, radiation exposure is low, and spatial resolution is superior. Cost and limited availability of the radiopharmaceuticals and PET equipment prohibit more widespread use of this imaging modality.

Octreoscan

Somatostatin receptor scintigraphy using octreotide has been used in patients with pheochromocytoma²⁰¹; however, the sensitivity of this imaging modality is low, especially in the detection of solitary tumors, and this modality is inferior to MIBG scintigraphy.²⁰¹ However, in patients with metastatic pheochromocytoma, Octreoscan can be useful, especially in those tumors that express somatostatin receptors and are negative on MIBG scintigraphy and 6-¹⁸F-fluorodopamine-PET.¹⁷³

Vena caval sampling for catecholamines and metanephrines is rarely called for except when extra-adrenal tumors have escaped removal during previous surgery and cannot be located with ^123/131I-MIBG scanning or other localizing techniques.¹⁶³

In summary, the strategies outlined above provide the basis for diagnostic localization of pheochromocytoma as described in Fig. 14-10. Although CT and MRI have excellent sensitivity, these anatomic imaging approaches lack the specificity required to unequivocally identify a mass as a pheochromocytoma. The higher specificity of functional imaging—the test of choice is currently ¹²³I-MIBG scintigraphy—offers an approach by which the limitations of anatomic imaging can be overcome.¹⁵⁴

Medical Therapy and Preparation for Surgery

Preoperative medical treatment is directed at controlling hypertension (including hypertensive crises during the removal of pheochromocytoma), maintaining stable blood pressure during surgery, and minimizing adverse effects during anesthesia and other clinical signs and symptoms caused by high plasma catecholamine levels.202,204

Maintenance of adequate blood pressure control for 2 weeks before the operation is an important aspect of management once a tumor is diagnosed. Phenoxybenzamine (Dibenzyline; irreversible noncompetitive α-adrenoceptor blocker) is used most commonly for preoperative blockade. Phenoxybenzamine has a long-lasting effect that diminishes only after de novo α-adrenoceptor synthesis. The initial dose of long-acting phenoxybenzamine is usually 10 mg twice a day; this is increased until clinical manifestations are controlled or side effects appear. For most patients, a total daily dose of 1 mg/kg is sufficient. Some patients may require much larger doses, and the dosage may be increased in increments of 10 to 20 mg every 2 to 3 days. If the drug is given in too high an initial dosage, the patient will have significant postural hypotension. As the correct dose is approached, paroxysmal hypertensive episodes will be brought under control, and when the right dose is achieved, the patient will become normotensive.

Other α-blocking agents of use are prazosin (Minipress), terazosin (Hytrin), and doxazosin (Cardura).²⁰⁵ All three are specific, competitive, and therefore short-acting α₁-adrenergic antagonists, and all three have the potential for severe postural hypotension immediately after the first dose, which therefore should be given just as the patient is ready to go to bed. Thereafter, the dosage can be increased as needed. Prazosin is administered in doses of 2 to 5 mg two or three times a day, whereas terazosin is given in doses of 2 to 5 mg once daily, and doxazosin in doses of 2 to 8 mg once daily. Labetalol (Normodyne or Trandate), a drug with both α- and β-antagonistic activity, may also be used at a dosage of 200 to 600 mg twice daily.²⁰⁶ Advantages of labetalol are that an α-blocker and a β-blocker are given simultaneously, and both oral and IV formulations of the drug are readily available. However, with labetalol, one is forced to use a fixed ratio of α- to β-antagonistic activity (i.e., 1:4 or 1:6). This often means that more slowing of the heart occurs, rather than control of hypertension, when what usually is needed is a drug with an α/β ratio of 4 : 1 or greater. It usually is better to use the amounts needed of individual α- and β-blockers. Large doses of any of these drugs may be necessary to control blood pressure. If blood pressure is controlled, and the patient is given a normal or high-salt diet, the patient’s diminished blood volume will be restored to normal. As normal blood volume is restored, the degree of postural hypotension decreases. β-Adrenergic blocking agents are needed only when significant tachycardia or a catecholamine-induced arrhythmia occurs. A β-blocker should never be used in the absence of an α-blocker because the former will exacerbate epinephrine-induced vasoconstriction by blocking its vasodilator component. This will make hypertensive episodes worse in subjects on a β-blocker alone.

In our experience, metyrosine (Demser) is a valuable drug in the treatment of patients with pheochromocytoma. The drug competitively inhibits tyrosine hydroxylase, the rate-limiting step in catecholamine biosynthesis.²⁰⁷ It significantly but not completely depletes catecholamine stores with maximum effect after about 3 days of treatment. Thus, it facilitates blood pressure control both before and during surgery, especially during the induction of anesthesia and surgical manipulation of the tumor—times when extensive sympathetic activation or catecholamine release may occur. Treatment is started at a dosage of 250 mg given orally every 6 to 8 hours; thereafter, the dose is increased by 250 to 500 mg every 2 to 3 days or as necessary up to a total dose of 1.5 to 4.0 g/day. The drug is a substituted amino acid (i.e., α-methyl-l-tyrosine), and therefore it readily crosses the blood-brain barrier. Thus, it inhibits catecholamine synthesis in the brain as well as in the periphery, and often causes sedation, depression, anxiety, and galactorrhea; it rarely causes extrapyramidal signs (e.g., Parkinsonism) in older patients. These symptoms are reversed rapidly when the dosage is lowered or the drug is discontinued. If dreaming abnormalities are reported by the patient, then the dosage should be reduced to the previous lower dose for 1 or 2 days, or until the abnormality disappears. Then the dosage should be increased more slowly until the desired effects are reached. Metyrosine is not generally available in all countries and institutions.

Various calcium channel blockers have been used to control blood pressure both before and during surgery.²⁰⁸ In our experience, if both metyrosine and α-antagonists are used, the blood pressure of the patient is much less labile during anesthesia and surgery, intraoperative blood loss is reduced, and less volume replacement is required during surgery than if only α-antagonists are used.²⁰⁹ It is our custom to administer 1 mg/kg of phenoxybenzamine and 0.5 to 0.75 g of metyrosine orally at midnight on the evening before surgery.

Hypertensive crises that can manifest as severe headache, visual disturbances, acute myocardial infarction, congestive heart failure, or cerebrovascular accident are appropriately treated with an intravenous bolus of 5 mg phentolamine (Regitine). Phentolamine has a very short half-life; therefore, if necessary, the same dose can be repeated every 2 minutes until hypertension is adequately controlled, or phentolamine can be given as a continuous infusion (100 mg of phentolamine in 500 mL of 5% dextrose in water). A continuous intravenous infusion of sodium nitroprusside (preparation similar to phentolamine) or, in some cases, nifedipine (10 mg orally or sublingually) can be used to control hypertension. Due attention should also be given to the possibility that some drugs (e.g., tricyclic antidepressants, metoclopramide, naloxone) can cause hypertensive crisis in patients with pheochromocytoma (Table 14-6).

In patients with clinical manifestations caused by β-adrenoceptor stimulation (e.g., tachycardia or arrhythmias, angina, nervousness), β-adrenergic receptor blockers such as propranolol, atenolol, or metoprolol are indicated. β-Adrenoceptor blockers, however, should never be employed before α-adrenoceptor blockers are administered, because unopposed stimulation of α-adrenoceptors and loss of β-adrenoceptor–mediated vasodilatation may cause a serious and life-threatening elevation of blood pressure. Labetalol, a combined α- and β-adrenoceptor blocker, is not preferred because in some patients it may cause hypertension (perhaps through its greater effect on β- than α-adrenoceptors).²¹⁰ It should be noted that both α- and β-adrenoceptor blockers may elevate plasma free normetanephrine levels.¹⁵⁰ In contrast, calcium channel blockers, also used to control hypertension and tachycardia in patients with pheochromocytoma, does not affect plasma metanephrine levels. A proposed algorithm for preoperative treatment is given in Fig. 14-11.²⁰²

For most abdominal pheochromocytomas smaller than 6 cm, laparoscopy has replaced laparotomy as the procedure of choice because of significant postoperative benefits.211,212

Postoperative Management

Volume replacement is the treatment of choice if hypotension should occur during surgery (i.e., after the tumor is removed) or in the postoperative period. The use of pressor agents is ill advised, especially if long-acting α-blockers have been used, because of the high doses of drug that must be used and the difficulty with which patients are weaned from these agents. Control of postoperative hypotension is even more imperative if both metyrosine and phenoxybenzamine are used preoperatively, because the former inhibits catecholamine synthesis by both the tumor and the sympathetic nervous system, whereas the latter blocks the action of any catecholamines that are synthesized. In this situation, the vascular bed is effectively paralyzed in a dilated state. Therefore, the best way to control blood pressure is via adequate volume replacement.

The volume of fluid required is often large (0.5 to 1.5 times the patient’s total blood volume) during the first 24 to 48 hours after removal of the tumor. This is because the half-lives of both metyrosine and phenoxybenzamine are approximately 12 hours, and thus it takes nearly three half-lives or 36 hours for the sympathetic nervous system to resume autoregulation. When this occurs, renal output begins to increase, and blood pressure and heart rate remain stable. It is at this time that normal replacement volumes (i.e., 125 mL/hr) can be used. If the last dose of medication was administered on the midnight before surgery, autoregulation usually occurs at about noon on the first postoperative day. Both the type and the amount of fluid replacement needed are readily determined by observation of the blood pressure, heart rate, central venous pressure, and urinary output. It is not unusual for patients to show a 10% to 12% increase in body weight by the time diuresis is begun.

Postoperative hypertension may mean that some tumor tissue was not resected. However, during the first 24 hours after surgery, hypertension is most likely attributed to pain, volume overload, or autonomic instability; these are all readily treated symptomatically. If hypertension persists in a patient even after he or she has returned to dry weight, the coexistence of essential hypertension is still the most likely diagnosis. However, any attempt to collect specimens for biochemical evidence of a residual tumor should be delayed at least 5 to 7 days post surgery to ensure that the large increases in both plasma and urinary catecholamines produced by surgery have dissipated. We normally repeat the postoperative urine collection just before the patient is to be discharged from the hospital, or when the patient is last seen by the surgeons 4 to 6 weeks post operation. Repeat measurements should be made if symptoms reappear, or approximately yearly, for a total of 5 years, if the patient remains asymptomatic. Operative mortality at the Mayo Clinic from 1980 to 1986 was 1.3%, or 1 in 77 patients.²¹³ The long-term survival of patients after successful removal of a benign pheochromocytoma is essentially the same as that of age-adjusted normal individuals.²¹⁴ At least 25% of patients remain hypertensive, but this is usually easily controlled with medication.^61,215

Malignant Pheochromocytoma

Malignant pheochromocytoma is established by the presence of metastases at the sites where chromaffin cells are normally absent.⁸³ Pheochromocytoma metastasizes via hematogenous or lymphatic pathways, and the most common metastatic sites are lymph nodes, bone, lung, and liver.^{159,168,216–218}Among all pheochromocytomas, the frequency of malignant pheochromocytomas ranges from 13% to 34%, with a slight male predominance.²¹⁸ It is recognized that one half of malignant tumors present are found at the initial presentation, whereas the second half develop at a median interval of 5.6 years.²¹⁹ The prevalence of an underlying SDHB mutation among patients with malignant pheochromocytoma is 30%, and even higher (48%) if the tumor originates from an extra-adrenal location.²²⁰ Two groups of patients can be distinguished on the basis of location of metastatic lesions. The first group represents short-term survivors with the presence of metastatic lesions, especially in liver and lungs. Their survival is usually less than 2 years. The second group represents long-term survivors with the presence of bone metastatic lesions. Patients in this group can survive longer than 20 years after the initial diagnosis. The overall 5-year survival rate varies between 34% and 60%.^171,221 The survival of patients with metastatic disease due to an underlying SDHB mutation is lower than in non-SDHB patients.²²² Recent advances in biochemical testing and nuclear imaging techniques, as discussed previously, have greatly improved our ability to diagnose and localize malignant pheochromocytoma at much earlier stages.

Clinical manifestations of malignant pheochromocytoma are similar to those of its benign counterpart, and no characteristic symptoms or group of symptoms would suggest a tentative diagnosis of malignancy.159,168,216–219 The most common manifestations are hypertension, headache, sweating, palpitations, and other symptoms. It should be noted that some patients have minimal symptoms despite markedly elevated catecholamine levels, most likely because of desensitization of adrenergic receptors by constant exposure to high concentrations of catecholamines. Furthermore, patients can present with symptoms caused by local invasion of tumors into various organs, especially in cases of SDHB-related disease.⁶²

Similar to benign pheochromocytomas, malignant pheochromocytomas predominantly secrete norepinephrine.42,165,223 However, patients with malignant disease tend to have higher levels of plasma and urinary metanephrines, reflecting a larger tumor size.^216,221 In addition, increased excretion of dopamine and its metabolites, VMA and 3-methoxytyramine, is often associated with malignant pheochromocytoma because of an intraneuronal loss of dopamine-β-hydroxylase as a consequence of cell dedifferentiation.^{42,168,171,219} The presence of normal epinephrine concentrations, together with that of excessive norepinephrine levels, also reflects tissue immaturity due to the tumor’s inability to N-methylate.²²³

Various attempts have been made to develop ancillary criteria to distinguish malignant from benign pheochromocytomas before they develop metastases. Young age, extra-adrenal tumor location, large tumor size, and adrenal pheochromocytomas that fail to take up MIBG all have been associated with an increased likelihood of malignancy.168,171,216,218,219,223 Persistent postoperative arterial hypertension is reported to be more common in malignant pheochromocytoma.¹⁷¹

Conventional pathologic features such as tumor necrosis, vascular or capsular invasion, nuclear atypia, and mitotic index do not consistently predict the malignant behavior of pheochromocytomas.168,171,216–219,223 In two different studies from the Mayo Clinic, pheochromocytomas that exhibited a diploid DNA pattern were associated with benign behavior, whereas a nondiploid DNA pattern seemed requisite for recurrence or metastasis.²²⁴ However, several studies thereafter did not confirm any correlation between DNA ploidy and malignant behavior in pheochromocytomas.^225,226 Several molecular markers for distinguishing benign from malignant pheochromocytomas have been investigated, but none appear to reliably indicate malignant behavior in an individual patient.^227–229 Therefore, long-term follow-up of patients with pheochromocytoma is mandatory.

As described previously, it is recognized that various peptides are produced and stored in the chromaffin granules in the adrenal medulla. In pheochromocytomas, these substances are secreted excessively, along with catecholamines. They may cause a systemic effect and may modify the clinical features of pheochromocytomas. In addition, they can be helpful (e.g., chromogranin A) in the diagnosis and follow-up of pheochromocytomas.²²⁷

Localization of malignant pheochromocytoma follows the same steps and algorithm as for benign pheochromocytoma. The exception (as described previously) is that malignant pheochromocytoma often may be dedifferentiated, thus losing the expression of cell membrane and vesicular transporter systems. In such a situation, FDG-PET can be more helpful than the use of a specific positron-emitting agent or MIBG scintigraphy, especially in SDHB-associated pheochromocytoma.¹⁹¹

Successful management of malignant pheochromocytoma requires a multidisciplinary approach.¹⁷⁴ Treatment is performed with the intention of attaining possible cure for limited disease and the goal of palliation for advanced disease. The treatment regimen should be individualized to meet the goal of controlling endocrine activity, decreasing tumor burden, and alleviating local symptoms.

Pharmacologic treatment for malignant pheochromocytoma does not differ from that provided for benign disease. For patients with limited disease, surgery may be the only curative modality of therapy. However, for patients with multiple metastatic lesions, radical surgical resection is often impossible, and other surgical procedures may be associated with complications such as those related to significant catecholamine release during tumor manipulation. Furthermore, at present it is not clear whether such an approach can prolong survival of patients; additional detailed, large, and prospective studies are needed. However, debulking often results in smaller tumor burden that may respond much better to radiotherapy and chemotherapy and a significant decrease in catecholamine levels, reflecting improvement of many symptoms and signs.

The first-line systemic treatment for malignant pheochromocytoma is targeted radiotherapy with the use of ¹³¹I-MIBG. ¹³¹I-MIBG therapy is used in MIBG-positive tumors, especially those that are unresectable. Doses vary from as low as 50 mCi up to 900 mCi as a single dose (such high doses require bone marrow rescue). However, more often, multiple doses of around 200 mCi are given at intervals of 3 to 6 months. The procedure is well tolerated, with minimal toxicity (if lower doses are used) that includes nausea; mild bone marrow suppression, especially thrombocytopenia; mildly elevated liver enzymes; and some renal toxicity. Thrombocytopenia usually is seen a few weeks after MIBG is administered. Patients take SSKI (100 mg three times a day) or potassium perchlorate (200 mg twice a day, if the patient is allergic to iodides), to block thyroid accumulation of radioiodine generated via deiodination of ¹³¹I-MIBG. Blocking medication is initiated 1 day before the patient receives ¹³¹I-MIBG and is continued for 30 days. Even with the blockade, some risk of decreased thyroid function is present. Overall, only one third of patients show partial response (less than 50% reduction of tumor mass) and improvement in symptoms and signs.²³⁰ Disease progression is common after 2 years. Use of higher doses of around 700 mCi may result in better response, but additional studies are needed.²³¹ Radiotherapy with the use of radiolabeled somatostatin analogues such as [¹¹¹In]-pentetreotide appears to be largely ineffective in metastatic pheochromocytoma.²³² In this context, [⁹⁰Y-DOTA]-D-Phe¹-Tyr³-octreotide requires further investigation.²³³

In rapidly progressive metastatic pheochromocytoma, chemotherapy rather than MIBG therapy is recommended. A combination of cyclophosphamide 750 mg/m² body surface area on day 1; vincristine 1.4 mg/m² on day 1; and dacarbazine 600 mg/m² on days 1 and 2 (CVD), administered IV in 21 day cycles, was used.²³⁴ Fifty-seven percent of patients had a complete or partial tumor response (i.e., at least a 50% reduction in the size of all measurable tumor). In addition, 79% of patients had a complete or partial biochemical response (i.e., at least a 50% reduction in urinary excretion of catecholamines and catecholamine metabolites). All responding patients showed objective improvement in performance status and in blood pressure, and the duration of response lasted from 6 months to over 2 years. Chemotherapy stops when the patient shows the development of new lesions or a 25% increase in the size of old lesions in spite of continued treatment. A major reason for the development of resistance of malignant pheochromocytoma to treatment with the CVD regimen is induction of MDR-1 gene activity. So far, attempts to block the activity of this gene have been unsuccessful. Data on alternative chemotherapy protocols remain limited. Very recently, a radiologic response was reported in one of three cases of metastatic pheochromocytoma among 29 patients with neuroendocrine tumors treated with an oral regimen of temozolomide (median dose, 150 mg/day) and thalidomide (median dose, 100 mg/day).²³⁵ Notable toxic effects in the whole study population included lymphocytopenia (69%), thrombocytopenia (14%), and neuropathy (38%).

Patients with large tumor burdens may present with massive release of catecholamines within the first few hours after administration of the first course of chemotherapy.²³⁶ A similar massive release of catecholamines was reported after chemotherapy with cyclophosphamide, vincristine, and prednisone in a patient with pheochromocytoma and lymphocytic lymphoma.²³⁷ These instances of “catecholamine storm” are manifested by the sudden onset of extreme tachycardia, severe hypertension, or both. Because these events are not predictable, we generally advise that the first course of chemotherapy, in any patient, be administered in hospital. It is important to intervene immediately with β-blockers if severe tachycardia occurs, or with α-blockers if extreme hypertension develops, or a combination of α- and β-blockers if both occur. Unless this is done rapidly, we have seen patients go into severe congestive heart failure with resultant decreases in cardiac ejection fraction to as low as 6% to 10%.²³⁶ These patients must not be abandoned at this point but must be given appropriate support. The catecholamine-stunned heart can respond, and we have seen recovery within 7 to 10 days.

In summary, no generally effective systemic treatment with antineoplastic potential is available for malignant pheochromocytoma. A considerable proportion of patients respond to MIBG radiotherapy or to cytotoxic chemotherapy. However, because there are no published randomized controlled studies, it remains unclear whether these responses have an overall impact on survival or quality of life. Fig. 14-12 shows a proposed algorithm for the treatment of metastatic pheochromocytoma.

External beam radiation is used for palliation of chronic pain and symptoms of local compression arising from these tumors.238,239 However, no systemic effects on tumor burden or hormone levels were observed. Successful infarction of pheochromocytoma by embolization has been demonstrated in individual case reports.²⁴⁰ Recently, radiofrequency ablation, cryotherapy, and percutaneous microwave coagulation have been used for treatment of malignant pheochromocytoma.^11,241,242

Pheochromocytoma in Children

Although pheochromocytomas are the most common endocrine tumors in children, they account for only 5% to 10% of all pheochromocytomas, with an incidence of 2 per million per year.243–245 In children, pheochromocytomas are commonly familial (40%), extra-adrenal (8% to 43%), bilateral adrenal (7% to 53%), and multifocal.^{106,246–249} Childhood pheochromocytomas peak at 10 to 13 years, with a male predominance (male vs. female, 2 : 1) before puberty.^106,246,250 Less than 10% of pediatric pheochromocytomas are malignant,^{106,246,251,252} with reported mean survival rates of 73% at 3 years and 40% to 50% at 5 years after diagnosis.^230,250,253 In 1960, Hume²⁵⁰ reported that 24% of pheochromocytomas in children are bilateral—a much higher incidence than is found in adults. Children also have a higher incidence of extra-adrenal pheochromocytomas, especially in the organ of Zuckerkandl and the urinary bladder. Recurrent pheochromocytomas are rare in children, but recurrent tumors may appear years after initial diagnosis, emphasizing the importance of close long-term follow-up.²⁵²

In contrast to adult patients, in whom sustained hypertension is found in only 50% of cases, more than 70% to 90% of children present with sustained hypertension.243,246,252 Pheochromocytoma is the underlying cause in 1% to 2% of cases of pediatric hypertension and should be considered after exclusion of more common causes such as renal disease and renal artery stenosis.¹⁰⁶ Pheochromocytomas secreting epinephrine may present with hypotension, particularly postural hypotension.⁴⁹ Sweating, visual problems, weight loss, and nausea and vomiting are more common in children than in adults,²⁵⁴ as are polyuria and polydipsia. In addition, children commonly present with palpitations, anxiety, and hyperglycemia.¹⁸ Other signs of catecholamine excess are pallor and flushing.¹⁸ As summarized by Manger and Gifford,¹⁸ some children occasionally present with a reddish blue mottling of the skin and a puffy red and cyanotic appearance of the hands. Less common clinical manifestations include fever and constipation. Similar to adult patients, the presence of the triad of headache, palpitations, and sweating in children, in combination with hypertension, should arouse immediate suspicion of a pheochromocytoma.

Because neuroblastomas (the most common solid tumors in childhood), ganglioneuroblastomas, and ganglioneuromas can synthesize and excrete catecholamines and their metabolites, the differential diagnosis of a pheochromocytoma is somewhat difficult or, at times, impossible.

Measurement of plasma free metanephrines under standardized conditions, with the use of age- and gender-specific reference ranges, appears to be the biochemical test of choice for detecting childhood pheochromocytoma.²⁵⁵

In children, more than 90% of pheochromocytomas are localized in the abdomen; therefore imaging studies should be directed to this part of the body. Although CT localizes about 95% of pheochromocytomas, MRI is the preferred imaging modality in children to avoid radiation exposure. MIBG scintigraphy is used to confirm that the tumor is indeed a pheochromocytoma and to rule out metastatic disease. We suggest genetic counseling and testing for underlying mutations in all children with pheochromocytoma.

Treatment of childhood pheochromocytoma is similar to that for pheochromocytomas that occur in adult patients.

Pheochromocytoma in Pregnancy

Pheochromocytoma in pregnancy demands special attention because it carries a high morbidity and mortality if pheochromocytoma is unsuspected (≈38% maternal mortality and ≈33% fetal mortality among published cases). Both maternal and fetal mortality can be greatly reduced if the diagnosis is made antenatally.256,257 Nevertheless, in two series it was found that pheochromocytoma remained unrecognized antepartum in 47% to 65% of patients.^256,257

Hypertensive crisis caused by pheochromocytoma in pregnancy is highly unpredictable. Direct tumor stimulation leading to marked catecholamine release can occur as the result of examination, postural changes, pressure from the uterus, labor contractions, fetal movements, and tumor hemorrhage. It is seen most commonly during the period surrounding delivery. Acute hypertensive crisis may manifest itself as severely elevated blood pressure, arrhythmia, or pulmonary edema.

The clinical picture of hypertensive crisis can be easily mistaken for acute toxemia of pregnancy. In contrast to acute toxemia, hypertension or hypertensive crisis can occur early in pregnancy (before the third trimester) and can be paroxysmal, or it may be accompanied by postural hypotension, in which proteinuria or edema is often absent.²⁵⁸ Biochemical diagnosis can be hindered if a patient is on methyldopa, which can result in a false-positive test. Therefore, if pheochromocytoma is suspected, treatment with methyldopa should be suspended or delayed for the measurement of metanephrines. The sensitivity of plasma metanephrines in the detection of pheochromocytoma appears to be maintained during pregnancy.

Localization of a suspected pheochromocytoma is vital and is best accomplished by MRI and/or ultrasonography. It is important to administer α-adrenergic blocking agents as soon as the diagnosis is confirmed. The agent of choice is phenoxybenzamine. With the exception of mild perinatal depression and transient hypotension in the newborn, no reports have described adverse fetal effects during treatment.²⁵⁹ β-Blockers have been used to control tachycardia, but they may be associated with intrauterine growth retardation.²⁵⁶

Approximately 25% of published cases presented with a cardiovascular emergency (e.g., myocardial ischemia, cardiac shock, pulmonary edema, cerebral hemorrhage). Maternal hypertensive crisis is always very dangerous for the fetus; it commonly results in uteroplacental insufficiency, early separation of the placenta, or fetal death.²⁶⁰ In situations of hypertensive crisis, IV phentolamine, given as a bolus of 1 to 5 mg or as a continuous infusion of 1 mg/min, can be used to control blood pressure. As a final resort, sodium nitroprusside may be used, but this has to be infused at a rate of less than 1 µg/kg/min to avoid fetal cyanide toxicity.²⁶¹

If the patient is in the first two trimesters, then the tumor should be removed as soon as the patient has been adequately prepared with α-blockers. Recently, this has been accomplished laparoscopically.²⁶² In most instances, the fetus will remain undisturbed, but a spontaneous abortion is possible. In the third trimester, it is appropriate for the patient to be treated with α-blockers and carefully monitored until the fetus reaches sufficient maturity to be viable. At that point, a cesarean section should be performed, because vaginal delivery can be extremely hazardous.^18,52,263 The tumor can be removed during the same operation. Anesthetic management is critical during the cesarean section and removal of the tumor, whether these procedures are done at the same time or in sequence.²⁶⁴ However, if uncontrolled hypertension, hemorrhage, or other emergency occurs, the tumor should be removed at once.^18,52 Magnesium sulfate has been used to control hypertensive emergencies during labor and during resection of the tumor in pregnant patients with pheochromocytoma.²⁶⁵ The efficacy of the drug was severely limited if an adequate blood level of magnesium could not be achieved because of preexisting hypomagnesemia. Labor and vaginal delivery should be avoided because these may cause tumor stimulation and increase catecholamine secretion with severe hypertensive crisis despite adrenergic blockade.

1. Manger, WM, Gifford, RW. Pheochromocytoma. J Clin Hypertens. 2002;4(1):62–72.

2. Pacak, K, Linehan, WM, Eisenhofer, G, et al. Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma. Ann Intern Med. 2001;134(4):315–329.

3. Brouwers, FM, Lenders, JW, Eisenhofer, G, et al. Pheochromocytoma as an endocrine emergency. Rev Endocr Metab Disord. 2003;4(2):121–128.

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