Chapter 11. Adrenal Medulla and Paraganglia

• ACE Angiotensin-converting enzyme
• ACTH Adrenocorticotropic hormone
• AM Adrenomedullin
• APMO Adnexal cystadenomas of probable mesonephric origin
• ARDS Acute respiratory distress syndrome
• ATP  Adenosine triphosphate
• cAMP Cyclic adenosine monophosphate
• CgA Chromogramin A
• CGRP  Calcitonin gene–related peptide
• COMT Catecholamine-O-methyltransferase
• DBH  Dopamine-β-hydroxylase
• FDG Fluorodeoxyglucose
• DHMA Dihydroxymandelic acid
• DHPG Dihydroxyphenylglycol
• ECD Electrochemical detection
• HIF Hypoxia-inducible factor
• HPLC High-pressure liquid chromatography
• IP3 Inositol triphosphate
• MAO Monoamine oxidase
• MEN Multiple endocrine neoplasia
• MHBA 3-methoxy-4-hydroxybenzylamine
• MIBG Metaiodobenzylguanidine
• NF-1 Neurofibromatosis type 1
• NSE Neuron-specific enolase
• PBSC Peripheral blood stem cell
• PNMT Phenylethanolamine- N-methyltransferase
• PTHrP Parathyroid hormone–related peptide
• RECIST Response evaluation criteria in solid tumors
• SDH Succinate dehydrogenase
• SDHB Succinate dehydrogenase subunit B
• SDHC Succinate dehydrogenase subunit C
• SDHD Succinate dehydrogenase subunit D
• SPECT Single photon emission computed tomography
• SRI Somatostatin receptor imaging
• VEGF Vascular endothelial growth factor
• VHL Von Hippel-Lindau
• VIP Vasoactive intestinal polypeptide
• VMA Vanillylmandelic acid (3-methoxy-4-hydroxymandelic acid)

The adrenal medulla and paraganglia are part of the autonomic/sympathetic nervous system. The endocrine and nervous systems are alike in that they exert their actions by releasing hormones/neurotransmitters that bind to cell surface receptors in the target tissue, thereby inducing an effect.

Autonomic nerves are not under conscious control. They innervate the heart, adrenal medulla, vascular smooth muscle, and smooth muscle in visceral organs, thereby controlling cardiac rate and output, adrenal medullary secretion of catecholamines, blood pressure, the genitourinary tract, and intestinal motility. Autonomic nerves originate within the central nervous system and have two major divisions according to their anatomic locations:

• (1) Parasympathetic preganglionic nerves exit the central nervous system via the cranial nerves and sacral spinal nerves. They terminate in nonchromaffin paraganglia that are most numerous in the neck and associated with the glossopharyngeal and vagus nerves. These ganglia serve as chemoreceptors that are involved in the control of respiration. An important paraganglion at the carotid bifurcation is known as the carotid body. They are also found along the jugular vein and in the jugulo-tympanic region. Head-neck paragangliomas are tumors that arise from these parasympathetic paraganglia.
• (2) Sympathetic preganglionic nerves exit the central nervous system via the thoracic and lumbar spinal nerves. The sympathetic nervous system coordinates the body's automatic fight-flight response by stimulating the adrenal medulla to secrete catecholamines and by directly stimulating cardiac output and blood flow to muscles while diverting blood flow away from visceral organs.

Sympathetic preganglionic nerves terminate mainly in paravertebral and prevertebral nerve ganglia where they secrete acetylcholine as their neurotransmitter; they are, therefore, known as cholinergic nerves. These nerve ganglia are collectively known as paraganglia and contain neuroendocrine cells that are similar to adrenal medullary cells on light microscopy by chromaffin and immunohistochemical staining. Paraganglia are also found in the mediastinum, particularly adjacent to the cardiac atria, and in the abdomen along the sympathetic nerve chains in paravertebral and prevertebral positions. Paraganglia are plentiful along the aorta, particularly around the celiac axis, adrenal glands, renal medullae, and aortic bifurcation (organ of Zuckerkandl). Paraganglia are also abundant in the pelvis, particularly adjacent to the bladder. Preganglionic nerves also terminate in the adrenal medulla, which is basically a sympathetic ganglion that is surrounded by adrenal cortex.

Sympathetic postganglionic nerve fibers originate from the paraganglia and run to the tissues being innervated. They secrete norepinephrine as their neurotransmitter at synaptic junctions. Adrenal medullary cells are basically modified postganglionic nerves that lack axons and secrete their neurotransmitter (mainly epinephrine) directly into the blood; thus, the bloodstream acts like a giant synapse, carrying epinephrine to receptors throughout the body. Synonyms for epinephrine and norepinephrine are adrenalin and noradrenaline, respectively (see later).

Although the adrenal medulla is not essential for survival, its secretion of epinephrine and other compounds helps maintain the body's homeostasis during stress. Investigations of the adrenal medulla and the sympathetic nervous system have led to the discovery of different catecholamine receptors and the production of a wide variety of sympathetic agonists and antagonists with diverse clinical applications.

Pheochromocytomas are tumors that arise from the adrenal medulla, whereas non–head-neck paragangliomas arise from extra-adrenal sympathetic ganglia. Pheochromocytomas can secrete excessive amounts of both epinephrine and norepinephrine, whereas paragangliomas secrete only norepinephrine. The excessive secretion of catecholamines can result in a dangerous exaggeration of the stress response.

Anatomy

Embryology

(Figure 11–1)

The sympathetic nervous system arises in the fetus from the primitive cells of the neural crest (sympathogonia). At about the fifth week of gestation, these cells migrate from the spinal ganglia in the thoracic region to form the sympathetic chain posterior to the dorsal aorta. They then begin to migrate anteriorly to form the remaining ganglia.

At 6 weeks of gestation, groups of these primitive cells migrate along the central vein and enter the fetal adrenal cortex to form the adrenal medulla, which is detectable by the eighth week. The adrenal medulla at this time is composed of sympathogonia and pheochromoblasts, which then mature into pheochromocytes. The cells appear in rosette-like structures, with the more primitive cells occupying a central position. Storage granules can be found in these cells at 12 weeks. The adrenal medullas are very small and amorphous at birth but develop into recognizable adult form by the sixth month of postnatal life.

Pheochromoblasts and pheochromocytes also collect on both sides of the aorta to form the paraganglia. These cells collect principally at the origin of the mesenteric arteries and at the aortic bifurcation where they fuse anteriorly to form the organ of Zuckerkandl, which is quite prominent during the first year of life. Pheochromocytes (chromaffin cells) also are found scattered throughout the abdominal sympathetic plexi as well as in other parts of the sympathetic nervous system.

Gross Structure

The anatomic relationships between the adrenal medulla and the adrenal cortex differ in different species. In mammals, the medulla is surrounded by the adrenal cortex, and in humans, the adrenal medulla occupies a central position in the widest part of the gland, with only small portions extending into the narrower parts. The mass of adrenal medullary tissue in both adult adrenal glands averages about 1000 mg (about 15% of the total weight of both adrenal glands), although the proportions vary from individual to individual. There is no clear demarcation between cortex and medulla. A cuff of adrenal cortical cells usually surrounds the central vein within the adrenal medulla, and there may be islands of cortical cells elsewhere in the medulla.

Microscopic Structure

The chromaffin cells or pheochromocytes of the adrenal medulla are large ovoid columnar cells arranged in nests, alveoli, or cords around a rich network of capillaries and venous sinusoids that drain blood from the adrenal cortex. Pheochromocytes have large nuclei and a well-developed Golgi apparatus. Their cytoplasm contains large numbers of vesicles (granules) that measure 100 to 300 nm in diameter and appear similar to the neurosecretory granules seen in peripheral sympathetic nerves. Catecholamines (epinephrine and/or norepinephrine) comprise about 20% of the mass of neurosecretory vesicles. Vesicles containing norepinephrine appear darker than those containing epinephrine. The vesicles also contain proteins, lipids, and adenosine triphosphate (ATP), as well as chromogranins, neuropeptide Y, enkephalins, and proopiomelanocortin (along with related peptides such as adrenocorticotropic hormone [ACTH] and β-endorphin).

Nerve Supply

The cells of the adrenal medulla are innervated by preganglionic fibers of the sympathetic nervous system, which release acetylcholine and enkephalins at the synapses. Most of these fibers arise from a plexus in the capsule of the posterior surface of the gland and enter the adrenal glands in bundles of 30 to 50 fibers without synapsing. They follow the course of the blood vessels into the medulla without branching into the adrenal cortex. Some reach the wall of the central vein, where they synapse with small autonomic ganglia. However, most fibers end in relationship to the pheochromocytes.

Blood Supply

The adrenal gland is perfused by the superior, middle, and inferior adrenal branches of the inferior phrenic artery, directly from the aorta and from the renal arteries. On reaching the adrenal gland, these arteries branch to form a plexus under the capsule supplying the adrenal cortex. A few of these vessels, however, penetrate the cortex, passing directly to the medulla. The medulla is also nourished by branches of the arteries supplying the central vein and cuff of cortical tissue around the central vein. Capillary loops passing from the subcapsular plexus of the cortex also supply blood as they drain into the central vein. Most of the blood supply to adrenal medullary cells is via a portal vascular system that arises from the capillaries in the cortex. There is also a capillary network of lymphatics that drain into a plexus around the central vein.

Norepinephrine is converted to epinephrine by the enzyme phenylethanolamine-N-methyltransferase (PNMT). In mammals, the expression of PNMT is induced by cortisol. Chromaffin cells that produce epinephrine are exposed to higher concentrations of cortisol from capillaries draining adrenocortical cells, whereas chromaffin cells containing norepinephrine are supplied by arteries that course directly to the adrenal medulla (see sections on biosynthesis and decretion, later).

The central vein of the right adrenal is short and drains directly into the vena cava with about 5% having multiple veins. About 5% of right adrenal veins drain into the hepatic vein. For the left adrenal gland, the vein is somewhat longer and drains into the left renal vein.

Catecholamines

Biosynthesis

(Figure 11–2)

Catecholamines are molecules that have a catechol nucleus consisting of benzene with two hydroxyl side groups plus a side-chain amine. Catecholamines include dopamine, norepinephrine, and epinephrine (see Figure 11–2).

Epinephrine is the main hormone secreted by the normal adrenal medulla. The proportions of epinephrine and norepinephrine found in the adrenal medulla vary with the species; in humans, the adrenal medulla contains 15% to 20% norepinephrine.

Norepinephrine is found primarily in the central nervous system and in peripheral sympathetic paraganglia and nerves. Dopamine is found in the adrenal medulla and in sympathetic neurons as a precursor to norepinephrine. It is present in high concentrations in the brain, in specialized neurons in the sympathetic ganglia, and in the carotid body, where it serves as a neurotransmitter. Dopamine is also present in the proximal renal tubule where it promotes sodium excretion and in the gastrointestinal tract where it serves a paracrine function.

Chromogranin A (CgA) is a peptide that is stored and released with catecholamines during exocytosis; catestatin is a fragment of the CgA prohormone that inhibits further catecholamine release by acting as an antagonist at the neuronal cholinergic receptor. CgA levels tend to be somewhat higher in patients with hypertension than in matched normotensive individuals. CgA has become a valuable tumor marker, particularly for patients with paragangliomas that are otherwise nonsecretory.

Conversion of Tyrosine to DOPA

The catecholamines are synthesized from tyrosine, which may be derived from ingested food or synthesized from phenylalanine in the liver. Tyrosine circulates at a concentration of 1 to 1.5 mg/dL of blood. It enters neurons and chromaffin cells by an active transport mechanism and is converted to l-dihydroxyphenylalanine (l-DOPA). The reaction is catalyzed by tyrosine hydroxylase, which is transported via axonal flow to the nerve terminal. Tyrosine hydroxylase is the rate-limiting step in catecholamine synthesis. It is transcriptionally activated by acetylcholine through the nicotinic cholinergic receptor, which in turn activates protein kinase A via cAMP. Tyrosine hydroxylase activity may be inhibited by a variety of compounds; alpha methyltyrosine (metyrosine) is an inhibitor that is sometimes used in the therapy of metastatic or unresectable pheochromocytomas.

Conversion of DOPA to Dopamine

DOPA is converted to dopamine by the enzyme aromatic l-amino acid decarboxylase (dopa decarboxylase). This enzyme is found in all tissues, with the highest concentrations in liver, kidney, brain, and vas deferens. The various enzymes have different substrate specificities depending on the tissue source. Competitive inhibitors of DOPA decarboxylase, such as methyldopa, are converted to substances (an example is α-methylnorepinephrine) that are then stored in granules in the nerve cell and released in place of norepinephrine. These products (false transmitters) were thought to mediate the antihypertensive action of drugs at peripheral sympathetic synapses but are now believed to stimulate the alpha receptors of the inhibitory corticobulbar system, reducing sympathetic discharge peripherally.

Conversion of Dopamine to Norepinephrine

Dopamine enters granulated storage vesicles where it is hydroxylated to norepinephrine by the enzyme dopamine-β-hydroxylase (DBH), which is found within the vesicle membrane. Norepinephrine is then actively transported into the vesicle by vesicular monoamine transferase (VMAT), which is located in the lipid bilayer of the vesicle wall. Norepinephrine constantly diffuses out of the vesicle, so it is best to consider it being concentrated in the vesicle, rather than being stored there. The granulated storage vesicle migrates to the cell surface and secretes its contents via exocytosis; both norepinephrine and DBH are released during exocytosis. After secretion, most norepinephrine is avidly recycled back into the nerve. Normally, about 93% of circulating norepinephrine originates from diffusion out of nonadrenal sympathetic nerve cells and synapses, while only 7% originates from the adrenal medulla.

Conversion of Norepinephrine to Epinephrine

Norepinephrine constantly diffuses out from storage granules into the cytoplasm. In most cells of the adrenal medulla, cytoplasmic norepinephrine is converted to epinephrine, catalyzed by PNMT. Epinephrine can then return to the vesicle, diffuse from the cell, or undergo catabolism. High concentrations of cortisol enhance the expression of the gene encoding PNMT. Cortisol is present in high concentrations in most areas of the adrenal medulla due to venous blood flow from the adjacent adrenal cortex. This accounts for the fact that in the normal human adrenal medulla, about 80% of the catecholamine content is epinephrine and only 20% is norepinephrine. In mouse models, the administration of exogenous corticosteroids appears to increase adrenal medullary PNMT expression, despite suppression of ACTH and endogenous adrenal cortisol production.

Paragangliomas rarely secrete epinephrine, because they do not have high local concentrations of cortisol to induce PNMT expression. Pheochromocytomas secrete epinephrine and norepinephrine in various ratios. Interestingly, after adrenalectomy, recurrent pheochromocytoma can secrete epinephrine without any surrounding adrenal cortex, indicating that the induction of PNMT may continue in subsequent cell lineages without high local levels of cortisol. After both adrenal glands are resected, serum epinephrine levels abruptly fall to nearly zero, whereas norepinephrine concentrations do not decline significantly, since most circulating norepinephrine originates from leakage out of sympathetic nerves and synapses.

The enzyme PNMT is found in many tissues outside the adrenal medulla. PNMT that is identical to adrenal PNMT has been found in the lung, kidney, pancreas, and cancer cells. Therefore, nonadrenal tissue is capable of synthesizing epinephrine if norepinephrine is available as a substrate. However, nonadrenal production of epinephrine usually contributes minimally to circulating levels. PNMT is found in human lung, and glucocorticoids increase its expression, thereby increasing lung epinephrine. This may possibly contribute to the bronchial dilation that is induced by glucocorticoids (inhaled or systemic). PNMT activity is also found in red blood cells, where its activity is increased in hyperthyroidism and decreased in hypothyroidism. Renal PNMT activity is such that up to one-half of the epinephrine found in normal urine may be the product of renal conversion from norepinephrine.

In the adrenal medulla, catecholamine stores can be depleted during prolonged hypoglycemia. Biosynthesis of catecholamines increases during nerve stimulation by activation of tyrosine hydroxylase. Prolonged stimulation leads to the induction of increased amounts of this rate-limiting enzyme.

Storage of Catecholamines

Catecholamines are not truly stored in intracellular vesicles. Rather, they exist in a dynamic equilibrium between the vesicle and the surrounding cytoplasm. Catecholamines continuously leak out of the vesicles into the cytoplasm but reenter and become concentrated in the vesicles by the action of two vesicular monoamine transporters: VMAT-1 and VMAT-2. Both are expressed in the adrenal medulla, but only VMAT-2 is expressed in sympathetic nerves.

In the adrenal medulla, the percentage of stored epinephrine (vs total catecholamines) varies widely among different species. In the human adrenal medulla, epinephrine comprises about 80% of stored catecholamines. Epinephrine and norepinephrine are stored in different cells. Morphologic differences in epinephrine and norepinephrine storage vesicles are visible on light microscopy after proper staining. Cells that store predominantly epinephrine tend to be adjacent to intramedullary sinusoidal vessels that bathe the cells in blood from the adrenal cortex; such blood contains cortisol that induces the enzyme PNMT that catalyzes the conversion of norepinephrine to epinephrine in the cytoplasm such that these vesicles contain predominantly epinephrine. Adrenal medullary cells that contain predominantly norepinephrine tend to be farther away from such vessels.

Norepinephrine is also found in the synaptic vesicles of postganglionic autonomic nerves in organs that have rich sympathetic innervations: the heart, salivary glands, vascular smooth muscle, liver, spleen, kidneys, and muscles. A single sympathetic nerve cell may have up to 25,000 synaptic bulges along the length of its axon; each synapse synthesizes norepinephrine and stores it in adrenergic synaptic vesicles adjacent to target cells.

Catecholamine biosynthesis is coupled to secretion, so that the stores of norepinephrine at the nerve endings remain relatively unchanged even in the presence of marked nerve activity. The adrenal medulla contains catecholamines at a concentration of about 0.5 mg/g; the spleen, vas deferens, brain, spinal cord, and heart contain 1 to 5 μg/g; and the liver, gut, and skeletal muscle contain 0.1 to 0.5 μg/g. Catecholamines are stored in electrondense granules approximately 1 μm in diameter that contain catecholamines and ATP in a 4:1 molar ratio, as well as several neuropeptides, calcium, magnesium, and water-soluble proteins called chromogranins (see earlier). The interior surface of the membrane contains DBH and ATPase. The Mg2+-dependent ATPase facilitates the uptake and inhibits the release of catecholamines by the granules. Adrenal medullary granules appear to contain and release a number of active peptides including adrenomedullin, ACTH, vasoactive intestinal peptide (VIP), chromogranins, and enkephalins. The peptides derived from chromogranins are physiologically active and may modulate catecholamine release.

Secretion of Catecholamines

(Figure 11–3 and Table 11–1)

Preganglionic nerve fibers terminate in adrenal medullary cells, where they release acetylcholine at synapses and stimulate adrenal medullary receptors. Activation of the receptors depolarizes the cell membranes and causes an influx of calcium ions. The increased intracellular concentration of calcium triggers exocytosis of the neurosecretory vesicles with consequent release of their contents: catecholamines, chromogranins, and soluble DBH. Vesicular membrane-bound DBH is not released during exocytosis.

Adrenal Medulla

In the adrenal medulla, exocytosis of the neurosecretory vesicles releases epinephrine and norepinephrine into the circulation. In normals, over 90% of circulating epinephrine is derived from the adrenal medulla, whereas adrenal medullary secretion accounts for only about 7% of circulating norepinephrine. Catecholamines also diffuse out of the neurosecretory vesicles into the cytoplasm. Catecholamines in the cytoplasm may reenter a vesicle via VMAT or may be metabolized by COMT into catecholamine metabolites: metanephrine and normetanephrine, which gradually diffuse out of the cell and enter the circulation.

Adrenal medullary catecholamine secretion increases with exercise, angina pectoris, myocardial infarction, hemorrhage, ether anesthesia, surgery, hypoglycemia, anoxia and asphyxia, and many other stressful stimuli. The rate of secretion of epinephrine increases more than that of norepinephrine in the presence of hypoglycemia and most other stimuli. However, during hypoxia, the adrenal medullary cells preferentially release norepinephrine. Such release is mainly not by exocytosis but rather by leakage of norepinephrine from neurosecretory vesicles into the cytoplasm and out of the cell into the circulation. The preferential release of norepinephrine may be because the adrenal medullary cells that concentrate norepinephrine are located farther from blood vessels and may be more susceptible to hypoxic injury. (See Storage of Catecholamines, earlier.)

Sympathetic Neurons

In sympathetic neurons, exocytosis of the neurosecretory vesicle releases norepinephrine into the synapse. Norepinephrine that has been secreted into a synapse by exocytosis is either reabsorbed via norepinephrine transporters (NETs) or leaks out of the synapse into the circulation. Such synaptic leakage accounts for the majority of circulating norepinephinre in normal individuals.

Metabolism and Excretion of Catecholamines

(Figure 11–4)

Catecholamine Metabolism in Cells of Origin

Adrenal Medulla

In the adrenal medulla, catecholamines are metabolized to metanephrines primarily by membrane-bound catecholamine-O-methyltransferase (COMT): epinephrine to metanephrine and norepinephrine to normetanephrine. The metanephrine metabolites subsequently leak into the circulation. Over 90% of circulating metanephrine and about 40% of circulating normetanephrine is produced by the adrenal medulla.

Sympathetic Nerves

Catecholamines that are released at the synapse bind to their receptors with relatively low affinity and dissociate rapidly (see Figure 11–4). About 10% of norepinephrine escapes from synapses into the systemic circulation (see later). About 90% of synaptic norepinephrine is reabsorbed by the nerves from which they were released or by the target cells. Cytoplasmic norepinephrine is metabolized to 3,4-dihydroxyphenylglycol (DHPG) at the outer mitochondrial membrane by the enzyme monoamine oxidase (MAO) that regulates the norepinephrine content of neurons. DHBG leaks from the neuron and is absorbed by the liver and other tissues that convert it to VMA (see later) that is excreted in the urine. In normals, most urinary VMA is derived from DHPG that leaks from sympathetic nerves.

Sympathetic nerves in abdominal organs, particularly the intestines and pancreas, account for nearly half the body's production of norepinephrine. Intestinal cells contain sulfatases that conjugate norepinephrine to norepinephrine-SO4 that enters the portal vein and bypasses the liver to be excreted in the urine. Intestinal cells also conjugate normetanephrine to normetanephrine-SO4.

Pheochromocytomas

In pheochromocytomas, catecholamines that leak out of the neurosecretory vesicles are methylated by membrane-bound COMT: epinephrine to metanephrine and norepinephrine to normetanephrine. These metanephrine metabolites continuously leak directly into the circulation, in contrast to catecholamines that are secreted intermittently. The pheochromocytoma's continuous excretion of metanephrines accounts for the superior sensitivity of plasma or urine-fractionated free metanephrine testing in the diagnosis of pheochromocytoma. In patients with pheochromocytoma, over 90% of circulating total metanephrines are derived from the tumor itself, rather than from peripheral metabolism.

Circulating Catecholamine Uptake and Metabolism

Following release into the circulation, catecholamines bind to albumin and other proteins with low affinity and high capacity. Catecholamines are quickly removed from the bloodstream and have a circulating half-life of less than 2 minutes. Although some free catecholamines are excreted directly into the urine, most are actively transported from the circulation into other cells where they are metabolized. Organic cation transporters (OCTs) are largely responsible for removing catecholamines from the circulation; they are expressed in many tissues, particularly the liver. Following active transport into a cell, catecholamines and their immediate metabolites undergo further metabolism. The main extra-adrenal/neuronal catecholamine metabolic pathway is initially via the enzyme MAO that converts both epinephrine and norepinephrine to DHPG. DHPG is further metabolized by soluble COMT to 3-methoxy-4-hydroxyphenylglycol (MHPG) that is converted by aldehyde dehydrogenase (AD) to vanillylmandelic acid (VMA) that is excreted in the urine.

Catecholamines, metanephrines, and MHPG also undergo conjugation of their phenolic hydroxyl group with sulfate or glucuronide; this reaction occurs mainly in gastrointestinal cells. To a lesser extent, catecholamines are also converted to metanephrines via a soluble form of COMT, an enzyme found in most tissues, especially blood cells, liver, kidney, and vascular smooth muscle. The soluble form of COMT is less active than the membrane-bound form of COMT found in the adrenal medulla and pheochromocytomas.

Catecholamines, their metabolites, and conjugates are excreted in the urine. Normally, the proportions of urine catecholamines and metabolites are approximately 50% metanephrines, 35% VMA, 10% conjugated catecholamines and other metabolites, and less than 5% free catecholamines.

Catecholamine (Adrenergic) Receptors

(Tables 11–2 and 11–3; Figures 11–5 and 11–6)

The adrenergic receptors are G protein–coupled receptors activated by norepinephrine and epinephrine. They mediate the sympathetic fight or flight response. The finding that most cells in the body have adrenergic receptors has led to an appreciation of the important regulatory role of the peripheral sympathetic nervous system and circulating catecholamines.

Adrenergic receptors were originally classified into two groups: α and β. This classification has been expanded as subtypes of the α and β receptors have been discovered and includes α1A, α1B, α1C, α2A, α2B, α2C as well as β1 and β2, and β3. Each receptor subtype is encoded by a different gene. Adrenergic receptors are variably distributed in the central nervous system and peripheral tissues.

Norepinephrine and epinephrine are roughly equipotent in activating α and β1 receptors. Epinephrine is much more potent in activating β2 receptors and norepinephrine is more potent in activating β3 receptors (Table 11–2). The physiologic effects mediated by them are summarized in Table 11–3.

Adrenergic receptors are transmembrane proteins with an extracellular amino terminus and an intracellular carboxyl terminus. Each of their seven hydrophobic regions spans the cell membrane. Although these regions of the adrenergic receptor subtypes exhibit significant amino acid homology, differences in the fifth and sixth segments determine the specificity of agonist binding. Differences in the fifth and seventh segments determine which of the guanylyl nucleotide binding proteins (G proteins) is coupled to the receptor. G proteins consist of α, β, and γ subunits. When a hormone binds to the receptor, the β and γ subunits dissociate from the α subunits, allowing GDP to be replaced by GTP on the α subunits and causing the β and γ subunits to dissociate from it. The GTP-bound α subunits activate the postreceptor pathways (see Figure 11–5).

Alpha-Adrenergic Receptors

Alpha1 receptors are Gq-coupled receptors with three homologous subtypes: α1A, α1B, and α1C. When an agonist binds to the α1 receptor, the alpha subunit of the guanylyl nucleotide-binding protein, Gq, is released and activates phospholipase C. This enzyme catalyzes the conversion of phosphatidylinositol phosphate to 1,4,5-inositol triphosphate (IP3) and diacylglycerol. IP3 releases calcium ion from intracellular stores to stimulate physiologic responses. Diacylglycerol activates protein kinase C, which in turn phosphorylates a series of other proteins that initiate or sustain effects stimulated by the release of IP3 and calcium ion (see Figure 11–5). Prazosin and phenoxybenzamine are selective antagonists of the α1 receptor.

Alpha1 receptors are postsynaptic (target organ) receptors that mediate diverse effects, particularly arteriolar vasoconstriction. Hepatic α1 receptors stimulate glycogenolysis and gluconeogenesis. In the eye, α1 receptors stimulate contraction of the radial muscle of the iris that dilates the pupil. In the skin, α1 receptors mediate apocrine sweating and pilomotor contraction. In the genitourinary tract, α1 receptors mediate ejaculation, gravid uterine contraction, and contraction of the bladder sphincter and trigone. In the intestines, α1 receptors reduce smooth muscle contraction and increase sphincter tone, thereby promoting constipation. Alpha1 receptors are also found in the splenic capsule and mediate the contraction of the capsule (particularly during hypoxia), which contracts the splenic volume up to 20% and can expel up to 125 mL of packed red blood cells into the circulation within 3 seconds of apnea.

Sympathetic nerves secrete norepinephrine into synaptic junctions where the concentration of norepinephrine is high, thereby stimulating synaptic effector organ α1 receptors. Epinephrine has a similar effect upon α1 receptors but is secreted only by the adrenal medulla such that circulating concentrations are usually much lower than concentrations of synaptic norepinephrine. At low plasma concentrations, epinephrine predominantly stimulates β2-adrenergic receptors (causing vasodilation, see later), whereas at higher plasma concentrations, epinephrine stimulates α1 receptors sufficiently to override vasodilation and cause vasoconstriction.

Alpha2 receptors are Gi coupled receptors with three highly homologous subtypes: α2A, α2B, and α2C. Agonist binding to the α2 receptor releases Gi alpha, which inhibits the enzyme adenylyl cyclase and reduces the formation of cAMP (Figure 11–6).

Presynaptic (nerve) α2 receptors are located near the synapses of sympathetic nerves. Synaptic norepinephrine binds to this receptor, resulting in feedback inhibition of its own release. Alpha2 receptors are also found in vascular smooth muscle where they mediate vasoconstriction. Alpha2 receptors in platelets stimulate platelet aggregation and clotting. In the brain, α2 receptors are found in the locus ceruleus, cerebral cortex, and limbic system. Although their location is postsynaptic, stimulation of the α2 receptors results in reduced release of norepinephrine. Clonidine is a central α2 agonist. Yohimbine is a selective antagonist for the α2 receptor. Phentolamine is an antagonist for both α1 and α2 receptors.

In the pancreatic beta cells, activation of α2 receptors inhibits insulin secretion. This causes glucose intolerance in patients with pheochromocytoma. The gene Adra2a encodes the adrenergic α2A receptor. A polymorphism in Adra2a increases the number of α2A receptors on beta cells, which reduces insulin secretion and increases the risk of type 2 diabetes mellitus.

Beta-Adrenergic Receptors

Beta-adrenergic receptors are postsynaptic (target organ) cell surface glycoproteins. Agonist binding to β-adrenergic receptors activates adenylyl cyclase via the Gs alpha subunit to increase the production of cAMP, which in turn converts protein kinase A to its active form. Kinase A then phosphorylates a variety of proteins, including enzymes, ion channels, and receptors (see Figure 11–6).

Beta1-adrenergic receptors are located primarily in the heart, kidneys, and adipose tissue. In the heart, β1 receptors are located in the SA and AV nodes, atrium, ventricle, and conduction system; activation of these receptors mediates an increase in heart rate and cardiac contraction with an overall increase in cardiac output. Stimulation of β1 receptors in the ventricles also increases the firing of idioventricular pacemakers such that excessive stimulation predisposes to ventricular ectopy. Triiodothyronine (T3) increases the total number of cardiac β1 receptors; this may contribute to the forceful cardiac contraction and tachyarrhythmias that are characteristic of hyperthyroidism. Beta1 receptors in the renal juxtaglomerular apparatus stimulate the release of renin that, in turn, activates the renin-angiotensin system. In fat cells, activation of β1 receptors increases lipolysis. In nerve cells, activation of β1 receptors increases nerve conduction velocity. In the brain, β1 receptors are found particularly in the nucleus accumbens and the ventral putamen (striatum).

Beta2-adrenergic receptors are particularly activated by epinephrine. They are located mainly in the smooth muscles of arterioles, veins, and bronchi where they mediate relaxation. In the heart, β2 receptors are located in the same locations as β1 receptors (see earlier) and likewise mediate increases in cardiac rate and contraction. β2 Receptors are also located in smaller coronary arteries where they mediate dilation of the coronaries, thereby increasing blood flow to cardiac muscle. Vascular β2 receptors mediate vasodilation of arterioles, particularly in skeletal muscle and the hepatic artery. Stimulation of venous β2 receptors mediates venous dilation. Stimulation of β2 receptors also causes relaxation of other smooth muscles, resulting in bronchial dilation and relaxation of the nonpregnant uterus. During exercise or hypoglycemia, epinephrine is secreted and activates hepatic β2 receptors. This stimulates glycogenolysis and gluconeogenesis for the increased glucose production that is needed for increased cardiac and skeletal muscle activity. Beta2 receptors in skeletal muscle promote increased contraction speed, glycogenolysis, and tremor. The net effect of β2 agonists (eg, epinephrine) upon liver and skeletal muscle is to increase serum glucose. Beta2-adrenergic receptors are also expressed in various areas of the brain, particularly the right hippocampus, which normally has a higher density of β2 receptors than the left hippocampus.

Beta2 receptor polymorphisms have been associated with obesity in women and differences in sensitivity to albuterol in asthmatics. Other β2 receptor polymorphisms appear to account for individual differences in the vascular response to stress and increased risk for development of hypertension-induced left ventricular hypertrophy.

Beta3-adrenergic receptors are expressed mainly in adipose tissue but also in the gallbladder, colon, central nervous system, and heart. Activation of this receptor increases energy expenditure, lipolysis, and intestinal motility. β3 receptor activation promotes lipolysis in adipose tissue and increased thermogenesis in skeletal muscle. Although β3-adrenergic receptors are found in the brains of infants, by adulthood their concentration decreases by 100-fold. Pima Indians, who are homozygous for inactivating mutations in the β3 gene, have an earlier onset of type 2 diabetes.

Dopamine Receptors

Five different dopamine receptors have been identified (D1 to D5), each encoded by a different gene. Dopamine receptors are found throughout the brain (including the anterior pituitary), arteries, proximal renal tubules, and gastrointestinal tract. D1 and D2 receptors are the predominant subtypes.

D1-like family of receptors (D1 and D5) couples to Gs that activates adenyl cyclase, thereby increasing intracellular cyclic AMP (cAMP). D1 receptors mediate vasodilation in the coronary, renal, cerebrovascular, and mesenteric arteries. D1 receptors in the proximal renal tubule enhance natriuresis. The D1 receptor is the most abundant dopamine receptor in the brain. Intravenous therapeutic dopamine at low doses predominantly stimulates D1 receptors, causing vasodilation. (However, high-dose therapeutic dopamine sufficiently occupies α and β receptors to cause vasoconstriction and increase blood pressure.) The A48G polymorphism of the D1 receptor gene has been associated with essential hypertension, with the 48G allele being found more frequently in hypertensive patients, presumably through a negative effect on the proximal renal tubule's excretion of sodium.

D2-like family of receptors (D2, D3, D4) couple to a different G protein, Gi that inhibits adenyl cyclase, thereby reducing intracellular cAMP, opening potassium channels, and decreasing the influx of calcium. D2 receptors are predominately presynaptic receptors that are located on sympathetic nerves. Activation of D2 receptors inhibits the synaptic release of norepinephrine and also inhibits the transmission of nerve impulses at sympathetic ganglia. Pituitary lactotroph cells also express D2 receptors, whose activation inhibits the secretion of prolactin. Activation of other D2 receptors in the brain causes vomiting. D2 receptors are also found throughout the stomach, small intestines, and proximal colon, where the dopaminergic system is believed to work in a paracrine fashion.

Regulation of Sympathoadrenal Activity

The rate of catecholamine secretion largely determines sympathoadrenal activity. However, adrenergic receptors and postreceptor events are sites of fine regulation.

As noted earlier, norepinephrine and epinephrine released during nerve stimulation bind to presynaptic alpha2 receptors and reduce the amount of norepinephrine released. CgA is secreted from neurosecretory vesicles, along with catecholamines. Catestatin, a fragment of CgA, blocks postreceptor cells' cholinergic receptors, thereby inhibiting sympathoadrenal activity.

The binding of a catecholamine agonist to its receptor reduces the number of receptors on the effector cell surface by a process called down regulation. Catecholamine receptor antagonists do not cause down regulation of receptor expression. The mechanisms involved in some of these changes are known. For example, phosphorylation of the β-adrenergic receptor by β-adrenergic receptor kinase results in sequestration of the receptors into membrane vesicles, where they are internalized and degraded. The phosphorylated receptor also has a greater affinity for β-arrestin, another regulatory protein, which prevents its interaction with Gsα.

Thyroid hormone increases the number of β receptors in the myocardium. Estrogen, which increases the number of alpha receptors in the myometrium, also increases the affinity of some vascular alpha receptors for norepinephrine.

Actions of Circulating Catecholamines

(Tables 11–3 and 11–4)

Norepinephrine activates α1-adrenergic receptors, increasing the influx of calcium into the target cell. Vascular α1-adrenergic receptors are found in the heart, papillary dilator muscles, and smooth muscle. Activation of α1-adrenergic receptors causes hypertension, increased cardiac contraction, and dilation of the pupils. Alpha1-adrenergic activation stimulates sweating from nonthermoregulatory apocrine stress sweat glands, which are located on the palms, axillae, and forehead. Norepinephrine also activates β1-adrenergic receptors that increase cardiac contraction and rate; stimulation of the heart rate is opposed by simultaneous vagal stimulation. Norepinephrine has less affinity for β2-adrenergic receptors. However, with higher circulating norepinephrine levels, hypermetabolism and hyperglycemia are noted. Norepinephrine also activates β3-adrenergic receptors on fat cells, causing lipolysis and an increase in serum levels of free fatty acids.

Epinephrine also stimulates α1- and β1-adrenergic receptors, with the same effects noted above for norepinephrine. However, epinephrine also activates β2 receptors, causing vasodilation in skeletal muscles. Epinephrine thus has a variable effect on blood pressure ranging from hypertension to hypotension (rare). Hypoglycemia is a strong stimulus for the adrenal medulla to secrete epinephrine, which increases hepatic glycogenolysis. Epinephrine stimulates lipolysis, resulting in increased serum levels of free fatty acids. Epinephrine also increases the basal metabolic rate. Epinephrine does not cross the blood–brain barrier well. However, high serum levels of epinephrine do stimulate the hypothalamus, resulting in unpleasant sensations ranging from nervousness to an overwhelming sense of impending doom.

Dopamine is an important central neurotransmitter and a precursor to norepinephrine and epinephrine. However, most circulating dopamine is actually derived from the gastrointestinal tract from local synthesis and dietary sources. Dopamine that is synthesized by the intestines does not function as a neurotransmitter but rather as a paracrine hormone, affecting intestinal motility, blood flow, and sodium transport. Dopamine is also synthesized in the proximal renal tubule where it is a natriuretic hormone. Dopamine synthesis is increased by a high-salt diet. The renal dopamine-paracrine system accounts for the relatively large amounts of dopamine that are normally found in the urine. Circulating dopamine is not normally a significant catecholamine. High serum concentrations of dopamine stimulate vascular D1 receptors, causing vasodilation and increased renal blood flow. Extremely high serum levels of dopamine are required to sufficiently activate vascular α1 receptors to cause vasoconstriction.

Physiologic Effects of Catecholamines

Cardiovascular Effects

The release or injection of catecholamines generally increases heart rate and cardiac output and causes peripheral vasoconstriction, leading to an increase in blood pressure. The infusion of catecholamines also leads to a rapid reduction in plasma volume. These events are modulated by reflex mechanisms, so that, as the blood pressure increases, reflex vagal parasympathetic stimulation may slow the heart rate and tend to reduce cardiac output. Although norepinephrine usually has these effects, the effect of epinephrine may vary depending on the smooth muscle tone of the vascular system at the time. For example, in an individual with increased vascular tone, the net effect of small amounts of epinephrine may be to reduce the mean blood pressure through vasodilation, despite an increase in heart rate and cardiac output. In an individual with a reduction in vascular tone, epinephrine increases blood pressure. In addition cardiovascular function is integrated by the central nervous system, so that, under appropriate circumstances, one vascular bed may be dilated while others remain unchanged. The central organization of the sympathetic nervous system is such that its basal regulatory effects are quite discrete—in contrast to periods of stress, when stimulation may be rather generalized and accompanied by release of catecholamines into the circulation.

Effects on Extravascular Smooth Muscle

Catecholamines have effects on smooth muscle in tissues other than blood vessels. These effects include contraction (α1) and relaxation (β2) of uterine myometrium, relaxation of intestinal and bladder smooth muscle (β2), contraction of the smooth muscle in the bladder (α1) and intestinal sphincters, relaxation of tracheal smooth muscle (β2), and pupillary dilation (α1).

Metabolic Effects

Catecholamines increase oxygen consumption and heat production. This effect is mediated by β1 receptors. Catecholamines also regulate glucose and fat mobilization from storage depots. Glycogenolysis in heart muscle and liver leads to an increase in available carbohydrate for utilization. Stimulation of adipose tissue leads to lipolysis and the release of free fatty acids and glycerol into the circulation. In humans, these effects are mediated by the β receptor. Both α1 and β2 receptors stimulate hepatic glycogenolysis and gluconeogenesis, which causes the release of glucose into the circulation. Both receptors are activated by epinephrine, which is particularly effective in raising hepatic glucose production. Plasma levels of catecholamines required to produce some cardiovascular and metabolic effects in humans are shown in Table 11–5.

Catecholamines have effects on water, sodium, potassium, calcium, and phosphate excretion in the kidney. Stimulation of the β1 receptor increases the secretion of renin from the renal juxtaglomerular apparatus, thereby activating the renin-angiotensin system. This leads to stimulation of aldosterone secretion.

Epinephrine and Norepinephrine Deficiency

Epinephrine is the major catecholamine secreted by the normal adrenal medulla, and its secretion is unique to the adrenal medulla. Epinephrine is usually deficient in cortisol deficiency of any cause, because high local concentrations of cortisol in the adrenal medulla are necessary for transcription of the enzyme PNMT, which catalyzes the conversion of norepinephrine to epinephrine in the catecholamine biosynthetic pathway. Primary autoimmune adrenal cortical insufficiency produces epinephrine deficiency. Hypothalamic/pituitary ACTH deficiency also causes cortisol deficiency and consequently epinephrine deficiency.

Autonomic Insufficiency

(Table 11–5 and Figure 11–6)

Autonomic insufficiency is also know as dysautonomia. It refers to a general reduction in autonomic activity. Since the adrenal medulla is part of the autonomic nervous system, there is usually an associated deficiency in circulating epinephrine. Autonomic insufficiency most commonly occurs in patients with long-standing type 1 diabetes mellitus. Diabetic autonomic neuropathy may be due to glucose neurotoxicity, but may also be due to autoimmunity. In one study of middle-aged patients with type 1 diabetes mellitus, 52% had complement-fixing antibodies against the sympathetic ganglia and 35% had antibodies against the adrenal medulla. They have minor defects in recovery from insulin-induced hypoglycemia (Figure 11–7), but in patients with diabetes mellitus in whom the glucagon response is also deficient, the additional loss of adrenal medullary response leaves them more susceptible to bouts of severe hypoglycemia. This is the result of a decrease in the warning symptoms as well as an impaired response to the hypoglycemia (see Chapters 17 and 18). Patients with generalized autonomic insufficiency usually have orthostatic hypotension. Familial dysautonomia can manifest as orthostatic tachycardia; norepinephrine transporter deficiency has been determined to be one cause of this condition. The causes of disorders associated with autonomic insufficiency are listed in Table 11–5.

When a normal individual stands, a series of physiologic adjustments occur that maintain blood pressure and ensure adequate circulation to the brain. The initial lowering of the blood pressure stimulates the baroreceptors, which then activate central reflex mechanisms that cause arterial and venous constriction, increase cardiac output, and activate the release of renin and vasopressin. Interruption of afferent, central, or efferent components of this autonomic reflex results in autonomic insufficiency.

Patients with generalized autonomic insufficiency usually have orthostatic hypotension; the reduction in blood pressure on standing that causes visual disturbances, lightheadedness, and even syncope. Symptoms tend to be worse upon awakening, after meals, in hot weather, and at high altitude. Many patients have supine hypertension, even when not taking hypertensive medication. Affected patients often have a fixed heart rate, sinus tachycardia, diminished sweating, reduced metabolic rate, heat intolerance, nocturia, and erectile dysfunction. Angina pectoris can sometimes occur in the absence of coronary atherosclerosis. Patients frequently have a neurogenic bladder with associated symptoms of frequency, nocturia, hesitancy, reduced urine stream, and recurrent urinary tract infections. Patients may also have gastroparesis and disordered gastrointestinal motility. Sleep apnea is common and death can occur during sleep from reduced respiratory drive.

The diagnosis of autonomic insufficiency can usually be made clinically in patients with typical symptoms and orthostatic blood pressure changes on examination. Additionally, plasma and urine norepinephrine levels are usually very low, sometimes only 10% of average normal in severely affected individuals. Plasma epinephrine levels are often low as well.

The treatment of symptomatic orthostatic hypotension is dependent on maintenance of an adequate blood volume. Physical measures should be employed, such as raising the foot of the bed at night, crossing the legs when sitting, and wearing full-leg fitted support stockings. Adequate hydration is important. Volume expansion with fludrocortisone is the most effective drug treatment. However, fludrocortisone can cause hypokalemia, supine hypertension, and edema. Midodrine is an α1-receptor agonist that must be administered every 8 hours, due to its short half-life of 3 to 4 hours. Midodrine's use is limited by common side effects that include severe supine hypertension, bradycardia, and erythema multiforme. Therefore, midodrine should only be used for patients with very symptomatic orthostatic hypotension who have failed other therapies. Octreotide has been used, either alone or in combination with midodrine, for patients with severe autonomic failure where other treatment measures have failed.

Both pheochromocytoma and non–head-neck paraganglioma are tumors of the sympathetic nervous system. Although they are similar tumors, they warrant distinction from each other to emphasize their differences in the following: (1) locations, (2) manifestations, (3) secretion profiles, (4) genetic syndromes, (5) difficulty of surgical resection, and (6) propensity to metastasize.

Pheochromocytomas are tumors that arise from the adrenal medulla, whereas non–head-neck paragangliomas arise from the ganglia of the sympathetic nervous system. Pheochromocytomas are more common (85%), and may be bilateral (17%). Patients with adrenal pheochromocytomas are less likely to develop detectable metastases (11%) compared to paragangliomas (30%).

Incidence

The yearly incidence of diagnosed pheochromocytoma/paraganglioma tumors is about 2 to 8 per million; nearly half of these present as an unexplained death. The National Cancer Registry in Sweden has reported that pheochromocytomas/paragangliomas are discovered in about 2 patients per million people yearly. However, autopsy series suggest a higher incidence. The reported incidence in autopsy series has varied from about 250 cases per million to 1300 cases per million in a Mayo Clinic autopsy series. Retrospectively, 61% of pheochromocytoma/paraganglioma tumors at autopsy occurred in patients who were known to have had hypertension; about 91% had the nonspecific symptoms associated with secretory pheochromocytoma/paraganglioma tumors. In one autopsy study, a large number of patients with these tumors had nonclassic symptoms such as abdominal pain, vomiting, dyspnea, heart failure, hypotension, or sudden death (Table 11–6). Considering these autopsy data, it is clear that the majority of pheochromocytoma/paraganglioma tumors are not diagnosed during life. Tumors occur in both sexes and at any age but are most commonly diagnosed in the fourth and fifth decades.

Pheochromocytomas are chromaffin tumors that arise from the adrenal medulla. They account for 90% of all pheochromocytoma/paraganglioma tumors in adults and 70% in children. Adrenal pheochromocytomas are usually unilateral (90%). Unilateral pheochromocytomas occur more frequently in the right (65%) versus the left adrenal (35%). Right-sided pheochromocytomas have been described as producing paroxysmal hypertension more often than sustained hypertension, whereas the opposite was true for tumors arising from the left adrenal. Adrenal pheochromocytomas are bilateral in about 10% of adults and 35% of children. Bilateral pheochromocytomas are particularly common (24% overall) in patients with familial pheochromocytoma syndromes caused by certain germline mutations (see later).

Basically, the adrenal medulla is a sympathetic ganglia whose neurons secrete neurotransmitters (epinephrine and norepinephrine) into capillaries instead of synapses. The adrenal medulla is surrounded by the adrenal cortex, with which it shares a portal system that bathes it in high concentrations of cortisol. Cortisol stimulates expression of the gene encoding PNMT, the enzyme that catalyzes the conversion of norepinephrine to epinephrine. Adrenal pheochromocytomas nearly always secrete catecholamines with variable amounts of epinephrine as well as norepinephrine and their metanephrine metabolites. Metastases from adrenal pheochromocytomas usually secrete only norepinephrine and its metabolite normetanephrine; they may rarely secrete epinephrine.

Pheochromocytomas are typically encapsulated by a true capsule or a pseudocapsule, the latter being the adrenal capsule. Pheochromocytomas are firm in texture. Hemorrhages that occur within a pheochromocytoma can give the tumor a mottled or dark red appearance. A few black pheochromocytomas have been described, with the dark pigmentation believed to be due to an accumulation of neuromelanin, a catecholamine metabolite. Larger tumors frequently contain large areas of hemorrhagic necrosis that have undergone cystic degeneration; viable tumor may be found in the cyst wall. Calcifications are often present. Pheochromocytomas can invade adjacent organs, and tumors may extend into the adrenal vein and the vena cava, resulting in pulmonary tumor emboli. Pheochromocytomas vary tremendously in size, ranging from microscopic to 3600 g. The average pheochromocytoma weighs about 100 g and is 4.5 cm in diameter.

Non–head-neck paragangliomas arise from sympathetic ganglia (Figure 11–8). They account for about 10% of all pheochromocytoma/paraganglioma tumors in adults and about 30% in children. About 75% are intra-abdominal where they are often mistaken for adrenal pheochromocytomas. Paragangliomas are sometimes nonsecretory and may be confused with other neuroendocrine tumors. They arise most commonly in the perinephric, periaortic, and bladder regions but often found in the chest (25%), arising in the anterior or posterior mediastinum or the heart. Pelvic paragangliomas may involve the bladder wall, obstruct the ureters, and metastasize to regional lymph nodes. About 36% to 60% of paragangliomas are functional, secreting norepinephrine and normetanephrine. Functional status is not known to affect survival. Nonfunctional paragangliomas can often concentrate metaiodobenzylguanidine (MIBG) or secrete CgA. Paragangliomas of the bladder can cause symptoms associated with micturition. Large perinephric tumors can cause renal artery stenosis and elevations in plasma renin activity. Vaginal tumors may cause dysfunctional vaginal bleeding. Paragangliomas can rarely arise in central nervous system locations, including the sella turcica, petrous ridge, and pineal region. Cauda equina paragangliomas can cause increased intracranial pressure.

Paragangliomas commonly metastasize (30%-50%) and present with pain or a mass. They tend to metastasize to the liver, lungs, lymph nodes, and bone. PGLs can be locally invasive and may destroy adjacent vertebrae and cause spinal cord and nerve root compression. PGL metastases usually secrete norepinephrine and normetanephrine. They do not secrete epinephrine and therefore do not typically cause significant weight loss, hyperglycemia, anxiety, or tremor.

Nonchromaffin parasympathetic paragangliomas are typically found in the head and neck. Unlike chromaffin sympathetic paragangliomas, only about 5% of these tumors secrete catecholamines. Carotid body tumors are paragangliomas that arise near the carotid bifurcation. They usually present as a painless neck mass, but can injure the vagus or hypoglossal nerves. Glomus tympanicum paragangliomas arise in the middle ear and cause tinnitus and hearing loss. The tumor may be seen as a reddish mass behind an intact tympanic membrane (red drum) that blanches when pressure is applied with a pneumatic ear speculum (Brown sign). Glomus jugulare paragangliomas arise in the jugular foramen. They often cause tinnitus and hearing loss as well as compression of cranial nerves, resulting is dysphagia. Vagal paragangliomas are rare, usually presenting as a painless neck mass often associated with hoarseness or dysphagia. Head-neck paragangliomas can also arise in the larynx, nasal cavity, nasal sinuses, and thyroid gland. Head-neck PGLs themselves are of more interest to otolaryngologists than endocrinologists. But they may be seen along with sympathetic paragangliomas in familial paraganglioma syndromes, particularly those with germline succinate dehydrogenase subunit D (SDHD) mutations (see later).

Nonchromaffin paragangliomas behave differently from sympathetic paragangliomas and pheochromocytomas, although they are embryologically related to chromaffin sympathetic paragangliomas and may arise concurrently with sympathetic paragangliomas in familial paraganglioma syndromes. These tumors are less likely to be malignant, although their indolence can be deceiving; recurrence and metastases may not appear for many years. Metastases to local nodes, lungs, and bone can occur. Long-term surveillance for recurrence or metastases is recommended for all patients. These tumors can produce CgA, and preoperative determination of CgA is recommended to determine if it will be a good serum marker for tumor recurrence. Patients with cervical paragangliomas often have an underlying germline mutation in the gene encoding succinate dehydrogenase (SDH); SDHD, SDHC, and SDHB gene sequencing is recommended for all these patients (see later). Individuals harboring a germline mutation must be screened for the existence of other paragangliomas and pheochromocytomas (see “Genetic Conditions Associated with Pheochromocytomas and Paragangliomas,” later).

Neuroblastomas, ganglioneuroblastomas, and ganglioneuromas are sympathetic nervous system tumors that are related to pheochromocytomas and likewise arise from embryonal sympathogonia (see Figure 11–1). Neuroblastoma is the most common malignant disease of infancy and the third most common pediatric cancer, accounting for 15% of childhood cancer deaths. Neuroblastomas are embryonal cancers of the postganglionic sympathetic nervous system and develop from sympathetic tissue in the adrenal gland, neck, posterior mediastinum, retroperitoneum, or pelvis. These tumors differ in their degree of maturation and malignancy. Neuroblastoma tumors derive from immature neuroblasts, are generally aggressive, tend to occur in very young children, and display clinical heterogeneity. The prognosis for neuroblastoma depends on age at diagnosis, with infants under age 1 year having a high likelihood of cure with surgical excision. Similarly, children with a localized neuroblastoma may be cured surgically. Some tumors can regress spontaneously or differentiate into benign ganglioneuromas. However, older children with widespread hematogenous metastases have a very poor prognosis, as do those whose neuroblastoma harbors an amplification of the Myc proto-oncogene. Some neuroblastomas are more indolent, depending on the nature of their oncogene mutations.

Ganglioneuroblastomas are composed of a mixture of neuroblasts and more mature gangliocytes; these develop in older children and tend to run a more benign course. Ganglioneuromas are the most benign of these tumors and are composed of gangliocytes and mature stromal cells.

Despite catecholamine secretion, children with neuroblastomas tend to be more symptomatic from their primary tumor or metastases than from catecholamine secretion. Tumors tend to concentrate radiolabeled MIBG, making it a useful imaging and therapeutic agent. Treatment of malignant tumors consists of surgery, chemotherapy, external beam radiation to skeletal metastases, and high-dose 131I-MIBG therapy for patients with MIBG-avid tumors.

Screening for Pheochromocytomas and Paragangliomas

Hypertension, defined as either a systolic or diastolic blood pressure over 140/90 mm Hg, is an extremely common condition, affecting about 20% of all American adults and over 50% of adults over 60 years of age. The incidence of pheochromocytoma is estimated to be less than 0.1% of the entire hypertensive population, but it is higher in certain subgroups whose hypertension is labile or severe. Screening for pheochromocytomas should be considered for such patients with severe hypertension and also for hypertensive patients with suspicious symptoms (eg, headaches, palpitations, sweating episodes, or unexplained bouts of abdominal or chest pains; Table 11–7).

Genetic Conditions Associated with Pheochromocytomas and Paragangliomas

(Tables 11–8, 11–9, 11–10, and 11–11)

Most pheochromocytomas occur sporadically, although a substantial proportion of these tumors are found to have developed a somatic mutation similar to those germline mutations that give rise to familial syndromes. Based on family history, it was formerly thought that only about 10% of patients with these tumors developed it as part of a genetic syndrome. With genetic testing, it is now clear that about 26% of patients with pheochromocytomas or paragangliomas carry a germline mutation associated with a familial syndrome. About 19% of patients with an apparently sporadic single pheochromocytoma and no known family history of pheochromocytoma harbor a germline mutation. For example, about 9% of patients with apparently sporadic, unilateral pheochromocytoma have been found to have von Hippel-Lindau (VHL) mutations. Genetic testing is advisable for all patients with a pheochromocytoma or paraganglioma. Genetic testing is strongly recommended for patients with extra-adrenal paragangliomas or multifocal tumors; onset of symptoms before age 45 years; prior history of head-neck paraganglioma; family history of paraganglioma, pheochromocytoma, or other tumors associated with MEN 2 or VHL. Genetic screening is also performed for patients with other manifestations of genetic syndromes noted later. Genetic screening can be done for MEN 2 RET proto-oncogene mutations, VHL mutations, and SDH (SDHB, SDHD, and SDHC) gene mutations. Neurofibromatosis is usually diagnosed clinically without genetic testing, since the NF-1 gene is very large.

Multiple Endocrine Neoplasia Type 2: RET Proto-Oncogene (10q11.2)

The first description of a pheochromocytoma was in a patient with MEN 2. In 1882, Felix Fränkel described pheochromocytomas in an 18-year-old woman with bilateral adrenal tumors; genetic testing of four living relatives has revealed a germline RET mutation.

The prevalence of MEN 2 has been estimated at 1 in 30,000. MEN 2 is an autosomal dominant disorder that causes a predisposition to medullary thyroid carcinoma, pheochromocytoma, and other abnormalities described later. MEN 2 is caused by an activating mutation in the RET proto-oncogene on chromosome 10q11.2. RET consists of 21 exons that encode a transmembrane receptor tyrosine kinase that is expressed in neural crest tissues. The constitutive activation of RET causes hyperplasia in affected tissues, including the adrenal medulla. Additional mutation(s) are believed to be required for a pheochromocytoma to develop. The somatic loss of a tumor suppressor gene on chromosome 1p appears to be necessary for pheochromocytoma formation. Additionally, reduced expression of NF-1 has been reported in a minority of pheochromocytomas arising in patients with MEN 2 mutations.

MEN 2 kindreds can be grouped into two distinct subtypes: MEN 2A (90%) and MEN 2B (10%). Patients with MEN 2A have various single amino acid missense mutations affecting the extracellular RET domain that cause RET homodimerization and constitutive activation of its tyrosine kinase. Patients with MEN 2B have a particular missense mutation (codon 918, exon 16) affecting the intracellular domain at the RET tyrosine kinase's catalytic site, causing constitutive activation. In either subtype, pheochromocytomas usually develop in the adrenals (96%); extra-adrenal paragangliomas are rare (4%). About 42% of patients with pheochromocytoma in MEN 2 have hypertension, usually paroxysmal. Overall, only about 53% exhibit symptoms of pheochromocytoma. Each specific type of mutation in the RET codon determines each kindred's idiosyncrasies, such as the age at onset and the aggressiveness of medullary thyroid carcinoma.

A limited number of RET gene exons have been found to harbor mutations that are capable of causing constitutive activation of the tyrosine kinase. RET exons 10, 11, 13, 14, 15, and 16 are usually involved. Therefore, routine genetic screening searches for mutations only in these exons. If no mutation is found in these exons, the remaining 15 exons can be sequenced in a research laboratory. When an affected kindred's RET mutation is already known, an individual in the kindred is screened for that specific mutation.

Pheochromocytomas arise in the adrenals, and extra-adrenal paragangliomas are rare in MEN 2. In patients with MEN 2, only about 4% of pheochromocytomas are found to be metastatic, possibly because of earlier detection. When pheochromocytomas develop in patients with MEN 2, they are bilateral in about two-thirds of cases; however, with close surveillance of affected kindreds, pheochromocytomas are discovered earlier and are more likely to be unilateral. After a unilateral adrenalectomy for pheochromocytoma in a patient with MEN 2, a contralateral pheochromocytoma develops in about 50% of patients an average of 12 years after the first adrenalectomy. In patients with MEN 2, adrenal pheochromocytomas produce norepinephrine and epinephrine (with its metabolite metanephrine). When screening for small pheochromocytomas, plasma catecholamine concentrations may be normal but plasma metanephrine concentrations are usually elevated, making plasma free metanephrines the screening test of choice for these patients. However, some pheochromocytomas are detected only by a 24-hour urine determination for fractionated metanephrines, catecholamines, and creatinine.

1. MEN 2A (Sipple syndrome)—Patients with this genetic condition develop medullary thyroid carcinoma (95%-100%), hyperparathyroidism due to multiglandular hyperplasia (35%), and pheochromocytoma (50%; range 6%-100% depending on the kindred) or adrenal medullary hyperplasia. Patients with MEN 2A also have an increased incidence of cutaneous lichen amyloidosis and Hirschsprung disease. Pheochromocytomas tend to present in middle age, often without hypertension. The incidence of hyperparathyroidism has also varied, averaging 35%.

   Individuals belonging to an MEN 2A kindred should have genetic testing for RET proto-oncogene mutations by 5 years of age to determine if they carry the genetic mutation that will require prophylactic thyroidectomy and close surveillance for pheochromocytoma and hyperparathyroidism.

   More than 85% of the mutations in MEN 2A families affect codon 634 in exon 11 of the RET proto-oncogene. Individuals with mutations in RET codon 630 also have a high incidence of pheochromocytoma. Pheochromocytomas also occur in most other kindreds with MEN 2A. Screening for pheochromocytoma should commence with the routine blood pressure measurements that are performed during examinations in childhood for medullary thyroid carcinoma and follow-up of hypothyroidism following thyroidectomy. At about age 15 years, affected individuals should commence yearly screening for pheochromocytoma with plasma free metanephrine determinations.

   Certain RET mutations (codons 609, 768, val804met, and 891) rarely produce pheochromocytomas. Less intense screening for pheochromocytomas is required in patients with these mutations.

2. MEN 2B—Over 90% of patients with MEN 2B have a single amino acid substitution of methionine to threonine on codon 918 in exon 16 that affects the intracellular domain of tyrosine kinase. About 50% of such mutations are familial while the rest arise de novo and are sporadic. Patients with this genetic condition are prone to develop mucosal neuromas, pheochromocytoma, adrenal medullary hyperplasia, and aggressive medullary thyroid carcinoma. About 50% of affected patients develop all three manifestations of the syndrome. Mucosal neuromas tend to develop first and occur in most patients. They appear as small bumps on the tongue, lips and buccal mucosa, eyelids, cornea, and conjunctivae. The lips and eyelids may become diffusely thickened. Intestinal ganglioneuromatosis occurs and alters intestinal motility, causing diarrhea or constipation and occasionally megacolon. Affected individuals have a marfanoid habitus with associated spinal scoliosis or kyphosis, pectus excavatum, a high-arched foot and talipes equinovarus (club foot) deformities. In patients with MEN 2B, medullary thyroid carcinoma tends to be aggressive and occurs at an earlier age than in patients with MEN 2A. Members of kindred with MEN 2B should immediately have genetic testing for their family's RET proto-oncogene mutation. If an individual is found to carry the family's RET mutation, early prophylactic thyroidectomy is advisable. In kindreds with MEN 2B, infants are screened for the mutation at birth. For affected infants, prophylactic thyroidectomy is performed by 6 months of age.

All individuals carrying a RET proto-oncogene mutation must have close medical surveillance (see Table 11–8). See Chapter 22: Multiple Endocrine Neoplasia.

Von Hippel-Lindau Disease: VHL Gene (3p25-26)

VHL disease is inherited as an autosomal dominant trait that predisposes its carriers to develop tumors in multiple tissues. Although certain VHL kindreds are predisposed to develop pheochromocytomas, it is not the dominant tumor of this syndrome. Pheochromocytomas develop only in patients with type 2 VHL (see later), and these are different from sporadic pheochromocytomas in that they are less likely to be malignant, more likely to be bilateral, and more likely to present at an earlier age. Although most VHL-associated pheochromocytomas arise in the adrenal, extra-adrenal paragangliomas sometimes arise; these usually occur along the sympathetic chain, but head-neck parasympathetic paragangliomas have been described. The mean age of presentation for a pheochromocytoma in type 2 VHL is 28 years; the youngest reported patient was 5 years old.

The different types and subtypes of VHL are as follows:

1. Type 1 VHL—Affected members of families with type 1 VHL do not develop pheochromocytomas. They tend to have loss-of-function VHL gene mutations, particularly gene deletions, frameshifts, or truncations.

2. Type 2 VHL—Affected members of families with type 2 VHL mutations are prone to develop pheochromocytomas. These patients carry VHL missense mutations. Type 2 VHL may be divided into subtypes as follows:

   1. Type 2A VHL—Pheochromocytomas, hemangioblastomas, low risk of renal cell carcinoma.

   2. Type 2B VHL—Pheochromocytomas, hemangioblastomas, high risk of renal cell carcinoma.

   3. Type 2C VHL—Pheochromocytomas, no hemangioblastomas, no renal cell carcinomas.

The prevalence of VHL is about 1 in 30,000 persons. VHL disease carriers are predisposed to multicentric hemangioblastomas in the retina (retinal angiomas), cerebellum, and spinal cord. Renal cysts and renal clear-cell carcinoma commonly develop.

Multiple cysts and nonfunctional neuroendocrine tumors may develop in the pancreas. Endolymphatic sac tumors may occur, resulting in hearing loss, vertigo, or ataxia. Adnexal cystadenomas of probable mesonephric origin (APMO) are found in many women with VHL. APMOs may develop in the ovary, broad ligament, vagina, uterine cervix, and vulva. Equivalent epididymal cystadenomas occur in men with VHL.

Genetic testing for VHL disease should be done in children born to a parent with known VHL disease. If VHL disease is suspected, but the family's VHL mutation is not known, the patient must be screened for point mutations by direct VHL gene sequencing of the entire coding region and splice junctions.

The clinical diagnosis of VHL disease is made when a patient with a known VHL gene mutation develops one tumor typical of VHL. In patients without a known family history of VHL, a presumptive diagnosis of VHL is made when they develop two or more hemangioblastomas or a hemangioblastoma in association with a pheochromocytoma or clear-cell renal carcinoma. Similarly, VHL disease should be suspected in patients with multiple VHL-associated tumors or one VHL-associated tumor that presents at a young age (<50 years for pheochromocytoma or hemangioblastoma; <30 years for clear-cell renal carcinoma). Such patients should have VHL gene sequencing.

The VHL gene is a tumor suppressor gene whose locus is 3p25/26. It encodes two different proteins (pVHL) of 213 and 160 amino acids. Both gene products have a role in the degradation of the hypoxia-inducible factors (HIF-1α and HIF-2α) as follows: The pVHL proteins have an α domain that binds with the protein elongin. The β domain of pVHL is open to bind HIF that has been hydroxylated, a reaction that requires oxygen. This complex then binds ubiquitin that targets HIF for intracellular destruction by proteases. In this manner, well-oxygenated cells destroy HIF. Conversely, cells that are either oxygen-deprived or that lack functional pVHL cause an intracellular accumulation of HIF. HIF is a transcription factor that induces the production of vascular endothelial growth factor (VEGF), erythropoietin, erythropoietin receptor, glucose transporter-1, and platelet-derived growth factor-B; these proteins allow an adaptation to hypoxia, but, in excess, they are believed to enhance tumorigenesis.

For a tumor to develop in a patient harboring a VHL germline mutation, an additional somatic mutation must develop in the patient's remaining wild-type VHL allele. This second-hit mutation must occur in a cell in susceptible somatic tissue (eg, vascular tissue) in order for the cell to grow into a VHL-associated tumor.

In patients with VHL disease, vascular tumors, particularly hemangioblastomas, renal cysts, and renal cell carcinomas, develop when there is a somatic second-hit on the wild-type allele in one cell; this can be caused by various spontaneous mutations (loss of heterozygosity) or promoter hypermethylation of the wild-type VHL allele. In these vascular tumors, a second-hit is usually necessary to cause sufficient accumulation of HIF to promote tumorigenesis. In contrast, pheochromocytomas that develop in patients with type 2 VHL typically have a normal wild-type VHL allele. However, most VHL-associated pheochromocytomas also demonstrate a somatic loss of chromosome 3 (94%) or chromosome 11 (86%).

A germline mutation in the VHL tumor suppressor gene has been identified in most families with VHL disease. About 60% of affected families have loss-of-function mutations (30% with truncated pVHL and 30% with large VHL gene deletions), resulting in type 1 VHL. About 40% have missense mutations, resulting in an amino acid substitution in pVHL, causing type 2 VHL.

In a French series of 36 patients with pheochromocytomas and VHL disease, pheochromocytomas were the presenting tumor in 53%. Pheochromocytomas tended to develop at an early age and were bilateral in 42%; concurrent paragangliomas were present in 11%. Three of the 36 patients had a malignant pheochromocytoma. In 18% of these patients with VHL disease, pheochromocytoma was the only known manifestation. Approximately 9% of patients with apparently sporadic, unilateral pheochromocytoma have been found to harbor a germline VHL mutation. In certain regions of Europe, the percentage is up to 20%, due to a founder effect for the Tyr98His black forest mutation that is more common in kindreds with German ancestry.

Pheochromocytomas in VHL disease produce exclusively norepinephrine. Therefore, the metabolite of norepinephrine (normetanephrine) is also produced in these tumors. Plasma normetanephrine levels are usually elevated when patients with VHL disease develop a pheochromocytoma. Therefore, it is advisable for patients with a type 2 VHL gene missense mutation to be screened regularly with plasma normetanephrine levels.

In patients with VHL, a major risk to life is the development of a renal cell carcinoma. When an abdominal computed tomography (CT) scan detects a solid renal lesion, it must be removed. Even simple cystic renal lesions are considered premalignant, and their removal is advisable if renal function can be preserved. If renal cysts are observed, they must be followed every 6 months with dynamic thin-section CT scanning to search for characteristics of malignancy: growth, wall irregularity, or septation. Individuals carrying a VHL mutation must have close medical surveillance. A surveillance protocol is recommended in Table 11–9.

Von Recklinghausen (Type 1) Neurofibromatosis: NF-1 Gene (17q11.2)

Pheochromocytomas are ultimately diagnosed in 0.1–5.7% of patients with von Recklinghausen neurofibromatosis type 1 (NF-1). Most of these pheochromocytomas are not diagnosed during life, since the autopsy incidence of pheochromocytoma in NF-1 patients is 3.3% to 13%. Pheochromocytomas that develop in patients with NF-1 are similar to sporadic pheochromocytomas: 84% have solitary adrenal tumors, 10% have bilateral adrenal tumors, 6% have extra-adrenal paragangliomas, and 12% have metastases or local invasion.

Pheochromocytomas are present in 20% to 50% of NF-1 patients with hypertension, and all NF-1 patients with hypertension must be screened for pheochromocytoma. It is prudent to screen all patients with NF-1 for pheochromocytoma yearly, with interval testing if hypertension or symptoms develop that are suggestive of pheochromocytoma (headache, perspiration, palpitations). Similarly, all patients with NF-1 should be screened for pheochromocytoma before major surgical procedures and pregnancy.

In patients with NF-1, pheochromocytomas can present anytime during life, from infancy to old age, with a mean age of 42 years at diagnosis. These pheochromocytomas can grow to large size. Although patients with pheochromocytomas may develop hypertension, many patients are surprisingly asymptomatic despite increased catecholamine secretion. Patients with NF-1 are prone to develop vascular anomalies such as coarctation of the aorta and renal artery dysplasia, which can produce hypertension and mimic a pheochromocytoma.

Von Recklinghausen disease is caused by a mutation in the NF-1 tumor suppressor gene mapped to chromosome 17q11.2. The NF-1 gene encodes a 2818 amino acid protein called neurofibromin, which inhibits Ras oncogene activity; loss of neurofibromin leads to Ras activation and tumor formation. It is a common autosomal dominant genetic disorder (although 50% of cases seem sporadic), with an approximate incidence of 300 to 400 cases per million population. Although genetic testing for NF-1 is available, the diagnosis is usually made clinically during childhood or adolescence.

Patients with NF-1 can present in childhood with optic gliomas that impair vision or in adolescence with plexiform neurofibromas. Patients develop visible subcutaneous neurofibromas and schwannomas of cranial and vertebral nerve roots. Skeletal abnormalities are common. Hypothalamic hamartomas may occur and cause precocious puberty. Iris hamartomas may occur and are known as Lisch nodules. NF-1 patients have an increased risk of developing other tumors, especially malignant peripheral nerve sheath tumors and leukemia (particularly juvenile chronic myelogenous leukemia). Patients may also have freckles in their axillae and skin folds. Multiple cutaneous pigmented café au lait spots develop and grow in size and number with age; most patients ultimately develop more than six spots (smooth bordered) measuring more than 1.5 cm in diameter.

Individuals carrying an NF-1 mutation must have close medical surveillance. A surveillance protocol is recommended in Table 11–10.

Familial Paraganglioma/Pheochromocytoma Syndromes: Succinate Dehydrogenase Gene Mutations

Certain kindreds have a proclivity to develop multicentric head-neck paragangliomas, sympathetic paragangliomas, and adrenal pheochromocytomas. These autosomal dominant syndromes were originally called familial paraganglioma syndromes, although some patients develop adrenal pheochromocytomas. The paraganglioma syndromes are caused by mutations in three of the four genes encoding mitochondrial complex II: SDH subunit B (SDHB, PGL 4), SDH subunit C (SDHC, PGL 3), and SDH subunit D (SDHD, PGL 1). (Note that PGL 2 is not caused by an SDH mutation.) SDHB encodes a catalytic subunit, while SDHC and SDHD encode membrane-anchoring subunits involved in electron transport. SDHC and SDHD (paternal) have an autosomal dominant proclivity to develop paragangliomas; those with SDHB and SDHD mutations can also develop adrenal pheochromocytomas. Individuals with SDHD mutations develop paragangliomas only if the mutated gene is inherited from the father (see later). Overall, about 12% of patients with paragangliomas and pheochromocytomas have been found to have germline SDH gene mutations.

Head-neck paragangliomas occur with an incidence of 10 to 33 cases per million persons. In one series of 34 patients with head-neck paragangliomas, 41% were found to have SDH germline mutations. Of those patients with germline mutations, 79% had SDHD mutations, and 21% had SDHB mutations.

These syndromes are caused by mutations in nuclear genes that encode three of the four subunits that comprise mitochondrial complex II (SDH) that oxidizes succinate to fumarate (Krebs cycle). The four subunits of the tetrameric SDH consist of a 70-kDa flavoprotein (SDHA), a 30-kDa iron-sulfur protein (SDHB), a 15-kDa subunit of cytochrome b (SDHC), and a 12-kDa subunit of cytochrome b (SDHD). SDHC and SDHD components of cytochrome b are integral mitochondrial membrane subunits anchoring the catalytic subunits SDHA and SDHB that are involved with the electron transport chain, transferring an electron to coenzyme Q (ubiquinone). SDH is essential for aerobic energy production and the tricarboxylic acid cycle. Genetic defects cause mitochondrial dysfunction making the cells functionally hypoxic. This leads to increased secretion of VEGF that is necessary for tumor growth. (SDHA germline mutations do not cause paragangliomas but rather cause Leigh syndrome, a fatal early-onset mitochondrial neurodegenerative disease.)

All patients with paragangliomas and pheochromocytomas ideally should be tested for germline mutations in SDH; such testing is highly recommended for patients with neck paragangliomas (> 15% have germline mutations), other paragangliomas (particularly multifocal paragangliomas or pheochromocytomas), a family history of paraganglioma or pheochromocytoma, and paragangliomas arising in patients with Dutch ancestry.

Carney-Stratakis syndrome: Some patients with loss-of-function mutations in SDHB, SDHC, or SDHD can develop the dyad of paragangliomas and gastric stromal sarcomas, which is known as Carney-Stratakis syndrome. Tumors present relatively early, with an average age of 24 years at diagnosis. Women and men are affected equally. The paragangliomas that develop in this syndrome are usually functional and develop in the abdomen, rather than head-neck region. In this syndrome, the condition is familial and affected kindreds do not develop pulmonary chondromas, factors that distinguish it from Carney triad.

1. SDHB gene mutations—The SDHB gene has been mapped to chromosome 1p36. This has also been described as familial paraganglioma syndrome type 4 or PGL 4. Affected individuals are prone to develop paragangliomas all along the sympathetic chains, from the neck to the pelvis, and can develop pheochromocytomas as well; they are less prone to glomus tumors of the neck than individuals with SDHD mutations. Paragangliomas that arise in patients with SDHB germline mutations are much more likely to be metastatic (35%) at the time of diagnosis than tumors seen in patients with SDHD germline mutations. In one kindred with a large SDHB exon 1 deletion, the phenotypic penetrance of paraganglioma was 35% by age 40. There have been no clear genotype-phenotype correlations with different SDHB mutations. However, certain kindreds have a distinctly higher penetrance. Also, some point SDHB mutations may be relatively benign genetic polymorphisms rather than pathological mutations. Due to the rarity of these tumors, the precise penetrance for each SDHB mutation has not been fully determined. Other malignancies may possibly be more common in patients with SDHB mutations. In one series of 53 patients, renal cell carcinoma was detected in two patients. Pediatric neuroblastoma has been described in a child with an SDHB exon deletion.

2. SDHC gene mutations—The SDHC gene has been mapped to chromosome 1q2. Affected individuals are prone to develop parasympathetic head-neck paragangliomas, but not pheochromocytomas. This is the least common SDH mutation. About 4% of patients with head-neck paragangliomas harbor an SDHC germline mutation.

3. SDHD gene mutations—The SDHD gene has been mapped to chromosome 11q23. Only patients with paternally inherited SDHD gene mutations are predisposed to develop paragangliomas and pheochromocytomas. Affected individuals are particularly prone to develop parasympathetic head-neck paragangliomas that do not typically secrete catecholamines. About 15% of patients with head-neck paragangliomas harbor this germline mutation.

In kindreds with SDHD gene mutations, only paternal transmission of the mutated gene causes the susceptibility to paragangliomas and pheochromocytomas; this phenomenon is known as maternal genomic imprinting, meaning that the maternally inherited mutant gene does not cause the syndrome in the mother's offspring. A male who inherits an SDHD mutation from his mother does not express the phenotype (ie, no paragangliomas) but can pass on the gene to his children, who can express the phenotype (paragangliomas). A female who inherits an SDHD mutation from her father develops paragangliomas, but her children who inherit the SDHD mutation are not affected.

Head-neck paragangliomas: Individuals with SDHD germline mutations are particularly prone to develop head-neck paragangliomas that arise from parasympathetic ganglia that are embryologically related to sympathetic paraganglia. These tumors do not usually secrete catecholamines and are known as nonchromaffin paragangliomas. Carotid body tumors are also known as chemodectomas and arise near the carotid bifurcation. They usually present as a painless neck mass but can injure the vagus or hypoglossal nerves. Glomus tympanicum paragangliomas arise in the middle ear and cause tinnitus and hearing loss. The tumor may be seen as a reddish mass behind an intact tympanic membrane. Glomus jugulare paragangliomas arise in the jugular foramen that often causes tinnitus and hearing loss as well as compression of cranial nerves, resulting is dysphagia. Vagal paragangliomas are rare, usually presenting as a painless mass in the neck that may cause hoarseness or dysphagia. Head-neck paragangliomas can also arise in the larynx, nasal cavity, nasal sinuses, and thyroid gland. Multicentric tumors have been reported in about 74% of paraganglioma patients with SDHD mutations. About 50% of patients with seemingly isolated pheochromocytomas and a germline SDHD mutation harbor a hidden paraganglioma. Sympathetic paragangliomas and adrenal pheochromocytomas (8%) also occur in affected individuals.

A founder SDHD mutation has been noted in families of Italian descent: Q109X. Three SDHD founder mutations have been discovered in families of Dutch ancestry: Leu95Pro, Asp92Tyr, and Asp92Tyr. An investigation of 243 family members with a paternally inherited Asp92Tyr mutation in SDHD reported the following. The risk of developing a paraganglioma or pheochromocytoma was 54% by age 40 years, 68% by 60 years, and 87% by 70 years. Most patients had head-neck paragangliomas, while some had sympathetic paragangliomas and 8% had pheochromocytomas. Multiple tumors were found in 65%.

Malignancy appears to be uncommon in patients with SDHD-associated paragangliomas. However, cervical paragangliomas can be indolent, and metastases to neck nodes, lungs, and bones may not be clinically evident for many years. Therefore, lifelong surveillance is necessary (Table 11–11).

Other Genetic Syndromes Associated with Pheochromocytoma or Paraganglioma

1. Carney triad—Multicentric paragangliomas occur in patients with Carney triad. While this is not a familial syndrome, it is believed to be genetic in origin. The underlying genetic defect is not known. Affected individuals can develop indolent gastric leiomyosarcomas, pulmonary chondromas, and paragangliomas (or adrenal pheochromocytomas). Only one-fifth of reported cases have had all three tumors, while most patients have had two of the three tumors, usually gastric sarcomas and pulmonary chondromas. Other tumors can develop in this syndrome, including adrenocortical adenomas (12%) and esophageal leiomyomas. Women account for 86% of the cases. Tumors tend to develop early in life, with an average age of 21 years at diagnosis.

2. Beckwith-Wiedemann syndrome—Pheochromocytomas have been reported in patients with Beckwith-Wiedemann syndrome and may be bilateral. Affected individuals also have other abnormalities, particularly neonatal hypoglycemia, omphalocele, umbilical hernia, macroglossia, and gigantism, and they are prone to develop malignancies.

3. Prolyl hydroxylase domain 2 (PHD2) gene mutations—PDH proteins regulate HIF. Germline mutations in PHD2 cause congenital erythrocytosis. An additional mutation of the wild-type PHD2 allele in paraganglia can give rise to a sympathetic paraganglioma. This gene mutation is different from VHL gene mutations, although both gene mutations cause an increase in HIF as a probable mechanism for paraganglioma tumor production.

4. KIF1B gene mutations—KIF1B is a gene that is believed to be a proapoptotic factor for sympathetic cell precursors. The gene is located on 1p36, where gene deletions have been noted in neural crest tumors. Mutations in KIF1B have been associated with pheochromocytomas, paragangliomas, and neuroblastomas, as well as other tumors that are not of neural crest origin. These tumors are transcriptionally related to NF-1 and RET tumors.

5. Familial paraganglioma syndrome type 2—One known kindred has a familial paraganglioma syndrome that has been labeled PGL2, but which is not due to an SDH mutation. This kindred harbors a mutation in the succinate dehydrogenase assembly factor 2 (SDHAF2) gene at 11q13.1.

Physiology of Pheochromocytoma and Paraganglioma

Pheochromocytomas are tumors that arise from the adrenal medulla, whereas paragangliomas arise from sympathetic nerve ganglia. Although some pheochromocytomas do not secrete catecholamines, most synthesize catecholamines at increased rates that may be up to 27 times the synthetic rate of the normal adrenal medulla (Figure 11–9). The persistent hypersecretion of catecholamines by most pheochromocytomas is probably due to lack of feedback inhibition at the level of tyrosine hydroxylase. Catecholamines are produced in quantities that greatly exceed the vesicular storage capacity and accumulate in the cytoplasm. Catecholamines that are in the cytoplasm are subject to intracellular metabolism to metanephrines; excess catecholamines and their metabolites diffuse out of the pheochromocytoma cell into the circulation.

In contrast to the normal adrenal medulla, most adrenal pheochromocytomas produce more norepinephrine than epinephrine, while many produce both hormones. Some pheochromocytomas produce epinephrine almost exclusively. Most paragangliomas produce mostly norepinephrine with some dopamine and no epinephrine. Paragangliomas that produce large amounts of dopamine tend to be metastatic. Some paragangliomas secrete no catecholamines or metanephrines.

Serum levels of catecholamines correlate only modestly with tumor size. On average, large tumors secrete more catecholamines than smaller tumors. However, large tumors are much more variable in their secretion of tumor markers. This may be due to the fact that larger tumors tend to develop hemorrhagic necrosis and cysts that are not functional. Additionally, about 20% of large, malignant paragangliomas are less differentiated and are nonsecretory.

Severe hypertensive episodes occur in most patients with pheochromocytomas. Exocytosis of catecholamines from the pheochromocytoma can play a role in such paroxysms, but most pheochromocytomas have minor sympathetic innervation. Instead, hypertensive crises are often caused by spontaneous hemorrhages within the tumor or by pressure on the tumor causing the release of blood from venous sinusoids that are rich in catecholamines. Thus, catecholamines can be released by physical stimuli such as bending or twisting or by micturition in patients with bladder paragangliomas. Of course, surgical manipulation of such tumors releases catecholamines and can cause life-threatening hypertensive crises.

Chronically high circulating levels of catecholamines may cause normal sympathetic axons to become saturated with catecholamines due to active catecholamine neuronal uptake. This may account for the paroxysms of hypertension that are triggered by pain, emotional upset, intubation, anesthesia, or surgical skin incisions. Adrenergic catecholamine saturation may also explain the elevations in plasma and urine catecholamines that can occur for 10 days or longer after a successful surgical resection of a pheochromocytoma.

Secretion of Other Peptides by Pheochromocytomas and Paragangliomas

(Table 11–12)

Although pheochromocytomas secrete mainly catecholamines and their metabolites, they also secrete many other peptide hormones, many of which contribute to a patient's clinical symptoms. Secretion of parathyroid hormone–related peptide (PTHrP) can cause hypercalcemia. Ectopic ACTH production can cause Cushing syndrome. Erythropoietin secretion can cause erythrocytosis. Leukocytosis is frequently seen in patients with pheochromocytoma, probably caused by cytokine release from the tumor. Interleukin-6 secretion can cause fevers and acute respiratory distress syndrome (ARDS).

Chromogranin A: Chromogranins are acidic single-chain glycoproteins that are found in neurosecretory granules. They have been categorized into three classes: chromogranins A (CgA), CgB (secretogranin I), and CgC (secretogranin II). In humans, the gene for CgA is on chromosome 14 and encodes a molecule with 431 to 445 amino acids. CgA molecules aggregate with low pH or high calcium concentrations and promote the formation of secretory vesicles and the concentration of hormones within these vesicles.

CgA also acts as a prohormone. It is cleaved by endopeptidases into smaller peptides. CgA is the prohormone for the amino terminal fragments vasostatin I (CgA 1-76) and vasostatin II (CgA 1-115), which appear to inhibit vasoconstriction. CgA is also the prohormone for catestatin (CgA 352-372), which blocks acetylcholine receptors and thus inhibits adrenosympathetic activity.

Most pheochromocytomas secrete CgA, and serum CgA levels may be assayed as a tumor marker for pheochromocytoma. However, CgA is not unique to the adrenal medulla. It is produced in neuroendocrine cells outside the adrenal medulla that secrete peptide hormones. CgA is found in the pituitary gland, parathyroid gland, central nervous system, and pancreatic islet cells.

Neuropeptide Y (NPY): Many pheochromocytomas secrete significant amounts of NPY. The molecule is a 36 amino acid peptide (see primary sequence later) that is found in neurosecretory granules and is secreted along with catecholamines. It is a very potent nonadrenergic vasoconstrictor that contributes to hypertension in some patients with pheochromocytoma.

• Tyr-Pro-Ser-Lys-Pro-Asp-Asn-Pro-Gly-Glu-Asp-AlaPro-Ala-Glu-Asp-Met-Ala-Arg-Tyr-Tyr-Ser-Ala-LeuArg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH2

NPY acts on G protein–coupled receptors, which belong to the pancreatic polypeptide family of cell-surface receptors called peptide YY (PYY). Six subtypes of these receptors have been identified (Y1R-Y6R). NPY has particular affinity for the Y1-R, Y2-R, Y3-R, and Y5-R receptors. Some PYY receptors are found in vascular smooth muscle and mediate NPY-induced vasoconstriction. Other PYY receptors are found on the pheochromocytes themselves and mediate NPY's autocrine effects: NPY appears to inhibit catecholamine synthesis via Y3R, a receptor which blocks L-type Ca2+ channels. It inhibits catecholamine release via Y2R, a receptor which blocks N-type Ca2+ channels.

NPY also has paracrine effects, stimulating endothelial cell proliferation and angiogenesis that may foster tumor growth. Patients with essential hypertension have normal levels of NPY. However, in a series of eight patients with pheochromocytomas, NPY levels were elevated 2- to 465-fold above the normal reference range. In another series, 59% of adrenal pheochromocytomas were found to secrete NPY during surgical resection; high serum levels of NPY were observed to correlate with vascular resistance, independent of norepinephrine. NPY appears to contribute to hypertension and left ventricular hypertrophy in most patients with pheochromocytoma. In contrast, few paragangliomas secrete NPY.

Adrenomedullin (AM): It was originally isolated from a pheochromocytoma, thus its misleading name. Although AM is produced by the adrenal medulla, it is also produced in the adrenal cortex (zona glomerulosa). It is produced by so many other tissues that the adrenal gland is actually a minor source for circulating AM.

AM is a 52 amino acid peptide cleavage product of a prohormone, preproadrenomedullin, encoded on chromosome 11. AM has some homology with calcitonin gene–related peptide (CGRP), and exerts its effects as a ligand for CGRP1 receptors and specific AM receptors. Ligand binding to the G protein–coupled receptors causes adenylate cyclase activation and an elevation of cellular cAMP levels.

AM is a pluripotent hormone. In the adrenal, AM appears to suppress aldosterone secretion. It is also secreted by the heart, lung, kidney, and brain as well as vascular endothelium, where it causes vasodilation. AM is also a natriuretic peptide and is secreted by the heart in congestive heart failure. AM is expressed in pheochromocytomas and a variety of other tumors, where it appears to stimulate tumor growth, reduce apoptosis, and suppress the immune response to the tumor.

Neuron-specific enolase (NSE): It is a neuroendocrine glycolytic enzyme. Serum levels of NSE have been reported to be normal in patients with benign pheochromocytoma but are elevated in about half of patients with malignant pheochromocytomas. Therefore, an elevated serum level of NSE increases the likelihood that a given pheochromocytoma is malignant.

Manifestations of Pheochromocytoma and Paraganglioma

(Table 11–13)

More than one-third of pheochromocytomas cause death prior to diagnosis. Death usually results from a fatal cardiac arrhythmia, myocardial infarction, or stroke. Adult patients with a pheochromocytoma usually have paroxysmal symptoms, which may last minutes or hours; symptoms usually begin abruptly and subside slowly. The particular constellation of symptoms varies considerably among patients. One cause for the differences in symptoms is the variable production of epinephrine and norepinephrine by these tumors. Pheochromocytomas that produce epinephrine tend to cause paroxysmal β-adrenergic manifestations, particularly anxiety, tremor, diaphoresis, tachycardia, palpitations, and hyperglycemia. Epinephrine and cytokine secretion can cause pulmonary edema and ARDS. Paragangliomas do not secrete epinephrine but most secrete norepinephrine that causes hypertension. Paragangliomas are more likely to metastasize.

Manifestations and their approximate incidence include hypertension (90%), headaches (80%), diaphoresis (70%), and palpitations or tachycardia (60%). Other common symptoms include episodic anxiety (60%), tremor (40%), abdominal or chest pain (35%), pallor (30%), and nausea or vomiting (30%). Hyperglycemia occurs in about 30% but is usually asymptomatic; diabetic ketoacidosis has been reported but is very rare. Patients may also experience fever (28%), fatigue (25%), flushing (18%), and dyspnea (15%). Change in bowel habits occurs frequently with either constipation (13%) or diarrhea (6%). Visual changes occur in 12% with either transient blurring or field loss during attacks; metastases to the orbit or skull base may directly impinge on the optic nerve. See Table 11–13.

Triggers for paroxysms: Episodic paroxysms may not recur for months or may recur many times daily. Each patient tends to have a different pattern of symptoms, with the frequency or severity of episodes usually increasing over time. Attacks can occur spontaneously or may occur with bladder catheterization, anesthesia, and surgery. Acute attacks may also be triggered by eating foods containing tyramine (the precursor to catecholamines): aged cheeses, meats, fish, beer, wine, chocolate, or bananas. Hypertensive crises can also be triggered by certain drugs: ionic radiocontrast media, MAO inhibitors, tricyclic antidepressants, sympathomimetics, decongestants, glucagon, chemotherapy, prednisone, ACTH, opiates, methyldopa, metoclopramide, nicotine, and cocaine. Phenothiazines have been reported to cause shock and pulmonary edema in patients with pheochromocytoma.

Paroxysms can be induced by seemingly benign activities such as bending, rolling over in bed, exertion, abdominal palpation, or micturition (with bladder paragangliomas). There is an amazing interindividual variability in the manifestations of pheochromocytomas. Most patients have dramatic symptoms, but other patients with incidentally discovered secretory pheochromocytomas are completely asymptomatic. Patients who develop pheochromocytomas as part of MEN 2 or VHL disease are especially prone to be normotensive and asymptomatic.

Blood pressure: Hypertensive crisis is the quintessential manifestation of pheochromocytoma. Blood pressure that exceeds 200/120 mm Hg is an immediate threat to life, being associated with encephalopathy or stroke, cardiac ischemia or infarction, pulmonary edema, aortic dissection, rhabdomyolysis, lactic acidosis, and renal insufficiency.

Definition of hypertension: In adults, hypertension is considered to be present when blood pressure exceeds 140 mm Hg systolic or 90 mm Hg diastolic. In children, blood pressure increases with age, such that maximal normal ranges are age dependent; hypertension is considered to be present when blood pressure measurements exceed the following: younger than 6 months, 110/60 mm Hg; 3 years, 112/80 mm Hg; 5 years, 115/84 mm Hg; 10 years, 130/90 mm Hg; and 15 years, 138/90 mm Hg.

Presentation of hypertension: Hypertension is present in 90% of patients in whom a pheochromocytoma is diagnosed. Hypertension occurs primarily from the secretion of norepinephrine. Epinephrine secretion variably increases blood pressure. Also, pheochromocytomas often secrete neuropeptide Y that is a potent vasoconstrictor. Some tumors may grow so large that they impinge upon the renal artery, causing increased renin production and secondary renovascular hypertension. Blood pressure patterns vary among patients with pheochromocytomas. Adults most commonly have sustained but variable hypertension, with severe hypertension during symptomatic episodes. Paroxysms of severe hypertension occur in about 50% of adults and in about 8% of children with pheochromocytoma. Other patients may be completely normotensive, may be normotensive between paroxysms, or may have stable sustained hypertension.

Hypertension can be mild or severe and resistant to treatment. Severe hypertension may be noted during induction of anesthesia for unrelated surgeries. Although hypertension usually accompanies paroxysmal symptoms and may be elicited by the above activities, this is not always the case.

Orthostasis: Patients with sustained hypertension frequently exhibit orthostatic changes in blood pressure, often with orthostatic tachycardia. Patients may complain of orthostatic faintness. Blood pressure may drop, even to hypotensive levels, after the patient arises from a supine position and stands for 3 minutes; such orthostasis, especially when accompanied by a rise in heart rate, is suggestive of pheochromocytoma. Epinephrine secretion from a pheochromocytoma may cause episodic hypotension and even syncope.

Hypotension and shock: Although hypertension is usually the key symptom in pheochromocytoma patients, hypotension and shock can occur. Some pheochromocytomas produce purely epinephrine that can produce mild hypertension from alpha stimulation but can also produce hypotension from predominantly beta-stimulated vasodilation. After a especially intense and prolonged attack of hypertension, shock may ultimately occur. This may be due to loss of vascular tone, low plasma volume, arrhythmias, or cardiac damage. Spontaneous necrosis within a pheochromocytoma can lead to severe hypotension when norepinephrine levels suddenly drop. Similarly, surgical resection of a pheochromocytoma often precipitates sudden and severe intraoperative hypotension, particularly in the presence of alpha blockade and other antihypertensives. Cardiogenic shock can occur as a result of cardiac ischemia or infarction as well as catecholamine cardiomyopathy. (See “Cardiac Manifestations,” later.)

Peripheral vasospasm and gangrene: Vasoconstriction is responsible for the pallor and mottled cyanosis that can occur with paroxysms of hypertension. Raynaud phenomenon can occur. Peripheral pulses may become thready or even nonpalpable during paroxysms. Catheters inserted into the radial artery and connected to continuous blood pressure monitoring transducers can give misleadingly low-pressure readings during paroxysms of vasospasm, a condition known as pseudoshock. Prolonged severe peripheral vasospasm has rarely caused gangrene of the skin, fingers, or toes. Reflex vasodilation usually follows an attack and can cause facial flushing.

Multisystem crisis: Massive release of catecholamines can occur spontaneously during tumor necrosis or can be triggered by any of the factors noted earlier. This can cause multisystem crisis that can be the presenting manifestation of pheochromocytoma, with hypertension or hypotension, high fever, encephalopathy, renal failure, ARDS, and death. Multisystem crisis resembles septic shock, so the diagnosis of pheochromocytoma may be missed entirely.

Cardiac manifestations: The heart is affected in most patients with pheochromocytoma, either directly from excessive catecholamines or indirectly from hypertension. Palpitation is one of the most frequent complaints.

Dysrhythmias: Tachycardia or dysrhythmias occur in about 60% of patients with pheochromocytoma. Patients may note palpitations, described variably as episodes of excessive heart pounding at rest or a fluttering sensation, during which they may become lightheaded. Supraventricular tachycardia is common, particularly in patients with epinephrine-secreting pheochromocytomas. The heart rate will often increase when standing. There can be an initial tachycardia during a paroxysm, followed by a reflex bradycardia. Atrial fibrillation may occur. Other dysrhythmias described with pheochromocytoma include nodal tachycardia, torsades de pointes, sick sinus syndrome, and Wolff-Parkinson-White (WPW) syndrome. Atrioventricular dissociation can occur and right bundle branch block has been reported. Ventricular tachycardia or ventricular fibrillation can occur suddenly and is a common cause of death.

Acute coronary syndrome (ACS): During a paroxysm, severe coronary vasospasm can cause myocardial ischemia or infarction, even in the absence of coronary atherosclerosis. This typically occurs simultaneously with increased myocardial oxygen demand caused by catecholamine-induced increases in heart rate and contractility. Patients may experience crushing chest pain or pressure with referred pain, usually to the jaw or the left shoulder or arm. Acute heart failure may occur along with severe hypotension or shock.

It can be difficult to distinguish ACS due to coronary stenosis/thrombosis from ACS due to a pheochromocytoma. Changes in the electrocardiogram and serum levels of troponin and creatine kinase-MB (CK-MB) are the same for both conditions. Patients with coronary disease can have tachycardia, cardiomyopathy, hypertension, dysrhythmias, diaphoresis, anxiety, and increased plasma catecholamine levels. However, patients with pheochromocytoma usually do not have critical coronary artery stenosis on coronary angiogram and usually have severe hypertension, headache, and other paroxysmal symptoms.

Cardiomyopathy: Left ventricular hypertrophy and hypertensive cardiomyopathy can occur in patients with chronic hypertension from pheochromocytoma. High levels of catecholamines can also directly cause myocarditis and a dilated cardiomyopathy. This is known as catecholamine cardiomyopathy. Takotsubo cardiomyopathy is the term used to describe asymmetric cardiac contractility with apical and midventricular akinesis or dyskinesis with hyperkinesis at the base. Other patterns of cardiac hypokinesis can occur. Most patients with catecholamine cardiomyopathy develop pulmonary edema and die. However, full recovery from cardiomyopathy may occur after treatment and surgical resection of a pheochromocytoma. In some patients, myocardial scarring and fibrosis lead to irreversible cardiomyopathy and heart failure. Fatal Takotsubo cardiomyopathy has been reported after dobutamine stress echocardiography.

There can be multiple causes of cardiomyopathy in patients with pheochromocytoma: hypertensive, ischemic, and catecholamine. The underlying pathophysiology of catecholamine cardiomyopathy appears to involve high levels of intracellular calcium in cardiac myocytes. Postmortem histopathology typically reveals intracardiac hemorrhages, edema, and concentrations of lymphocytes and leukocytes in cardiac muscle with areas of myocardial fibrosis.

Cardiac paragangliomas: These are rare tumors that arise at the base of the heart near the trunks of the aortic and pulmonary arteries and may be asymptomatic or cause hypertension and palpitations. They typically involve the left atrium or interatrial groove and often protrude into the atrium, resembling an atrial myxoma. Cardiac paragangliomas often have an invasive intramural component, making tumor resection difficult.

Diaphoresis and fever: During a paroxysm, sweating usually occurs initially from apocrine glands, affecting the palms, axillae, head, and shoulders. Reflex thermoregulatory eccrine sweating occurs later in an attack, dissipating the heat that was acquired during the prolonged vasoconstriction that occurred during the paroxysm. This can cause drenching sweats, usually as a paroxysm subsides. Patients with pheochromocytoma commonly develop fevers that may be mild or severe, even as high as 41°C. Up to 70% of patients have unexplained low-grade elevations in temperature of 0.5°C or more. Such fevers have been attributed to the secretion of interleukin-6 and respond to NSAID therapy.

Gastrointestinal manifestations: Many patients with pheochromocytoma exhibit gastrointestinal symptoms such as abdominal pain, nausea, and vomiting. Most patients lose some weight, even if appetite is preserved. More severe weight loss (> 10% of basal weight) occurs in about 15% of patients overall and in 41% of those with sustained and prolonged hypertension. Abdominal pain may be due to splanchnic vasoconstriction (intestinal angina) and prolonged vasospasm can cause ischemic enterocolitis. Vasospasm can rarely cause ischemic gangrene of the bowel. Pain may also be caused by the growth of a large intra-abdominal tumor. Intestinal motility disorders are also common. Catecholamines relax gastrointestinal smooth muscle while increasing contraction of the pyloric and ileocecal sphincters. Constipation is common, and abdominal distention and even toxic megacolon can occur. Other abdominal emergencies can be seen with pheochromocytoma, including the rupture of an aortic aneurysm, acute cholecystitis, and acute pancreatitis.

Neurologic manifestations: Headache is a common manifestation during an acute paroxysms. Patients frequently complain of paresthesia, numbness, or dizziness. Affected patients have an increase risk of experiencing a cerebrovascular accident (CVA) or transient ischemic attack (TIA). Hemiplegia can occur, sometimes with homonymous hemianopsia, and may be transient or permanent. Although most CVAs are ischemic in origin, hemorrhagic stroke can also occur during hypertensive paroxysms. Rupture of the internal carotid artery into the cavernous sinus can occur, causing a third nerve palsy. Some patients develop confusion or even psychosis during paroxysms. Paresthesias can occur.

Pulmonary manifestations: Patients may complain of dyspnea during a paroxysm. Patients with catecholamine cardiomyopathy may also present with dyspnea. Some patients develop ARDS, which can develop acutely or over several days. This is a life-threatening condition but may be self-limited during an attack. Isolated adrenal pheochromocytomas can produce ARDS. Patients with large hepatic metastases may be more prone to develop this complication. It may be mistaken for pneumonia, pulmonary edema, pulmonary emboli, or congestive heart failure. It is hypothesized that ARDS is caused by interleukin-6 produced by the tumor. Congestive heart failure may also cause pulmonary edema and can be distinguished from ARDS by echocardiogram.

Renal manifestations: Some degree of renal insufficiency is common in patients with pheochromocytoma. Hypertensive nephrosclerosis occurs in patients with a long history of severe hypertension. Nephrotic syndrome may occur with significant proteinuria, possibly due to secretion of interleukin-6 by the tumor. Malignant nephrosclerosis can occur with severe hypertension damaging renal arterioles, resulting in rapidly progressive renal failure. Large pheochromocytomas and perirenal paragangliomas can impinge upon the renal artery, causing increased renin production and a Goldblatt kidney, resulting in renovascular hypertension that is additive to norepinephrine-induced hypertension. The tumor may directly invade the renal vein and extend into the inferior vena cava, causing pulmonary emboli and an increased risk of lower extremity deep vein thrombosis. Severe hypertensive paroxysms can cause muscle ischemic damage and rhabdomyolysis with release of myoglobin that causes myoglobinuric renal failure. Acute tubular necrosis can occur after a severe hypotensive episode.

Ectopic hormone production: Pheochromocytomas can rarely produce ACTH that stimulates the adrenal cortex to produce excessive cortisol, resulting in Cushing syndrome. Tumors can also produce VIP that can cause watery diarrhea, hypokalemia, and achlorhydria, the WHDA (Verner-Morrison) syndrome. Some tumors produce PTHrP that causes hypercalcemia. Although pheochromocytomas can secrete renin directly, elevated plasma renin levels are usually derived from the juxtaglomerular apparatus, whose β1 receptors are stimulated by both epinephrine and norepinephrine.

Manifestations in children: The symptoms of pheochromocytomas in children are different from those in adults. Over 80% of children exhibit hypertension that is usually sustained and less frequently (10%) paroxysmal. Children are more prone to diaphoresis and visual changes. Children are more likely to have paroxysms of nausea, vomiting, and headache, which often occur after exertion. They are also prone to weight loss, polydipsia, polyuria, and convulsions. Affected children may also exhibit reddish-blue mottled skin along with edematous and cyanotic-appearing hands, a symptom rarely seen in adults. Children are more likely to have multiple tumors and extra-adrenal paragangliomas. In one series, 39% of affected children had bilateral adrenal pheochromocytomas, an adrenal pheochromocytoma plus a paraganglioma, or multiple paragangliomas; a single paraganglioma occurred in an additional 14% of children. Affected children often have genetic conditions associated with pheochromocytomas and paragangliomas. Thus, they may harbor the other tumors associated with these conditions. All affected children should have genetic testing for mutations in VHL, RET, SDHB, and SDHD (see earlier).

Manifestations in women: There are sex differences in pheochromocytoma symptomatology, with women tending to be more symptomatic than men. Women report significantly more headache (80% vs 52%), weight change (88% vs 43%), numbness (57% vs 24%), dizziness (83% vs 39%), tremor (64% vs 33%), anxiety (85% vs 50%), and changes in energy level (89% vs 64%).

Manifestations in pregnancy: A pheochromocytoma during pregnancy can cause sustained hypertension or paroxysmal hypertension that is typically mistaken for eclampsia. Hypertensive paroxysms tend to occur more frequently as the uterus enlarges, triggered by direct pressure upon the tumor by shifts in position or movement of the fetus. Hypertensive crisis typically occurs at the time of vaginal delivery and is commonly associated with cardiac arrhythmia, ARDS, and death. Postpartum women may develop shock or fever that can mimic uterine rupture, amniotic fluid embolus, or infection (puerperal sepsis). A tumor that is unrecognized carries a grave prognosis, with a reported 40% maternal mortality and a 56% fetal mortality. If the diagnosis of pheochromocytoma is made before delivery, the maternal mortality rate drops to about 10%. (See “Pregnancy and Pheochromocytoma,” later in the chapter.)

Manifestations of malignancy: Metastases occur in about 10% of pheochromocytomas and 30% of non–head-neck sympathetic paragangliomas. Since histopathology cannot distinguish whether a given pheochromocytoma is malignant, the term malignant is dependent upon whether metastases are detectable at presentation (50%) or months to years later (50%). Metastases are usually (80%) functional and can cause recurrent hypertension and symptoms many months or years after an operation that had been thought to be curative. (See “Metastatic Pheochromocytoma and Paraganglioma” discussed later.)

Normotension Despite High Plasma Levels of Norepinephrine

Interestingly, about 14% of patients with pheochromocytomas and paragangliomas have no hypertension despite having chronically elevated serum norepinephrine levels. This phenomenon has been variably called desensitization, tolerance, or tachyphylaxis.

Patients can be genetically prone to adrenergic desensitization. Adrenergic desensitization is caused by adrenergic receptors undergoing sequestration, downregulation, or phosphorylation. Adrenergic desensitization appears to be one cause of the cardiovascular collapse that can occur abruptly following the removal of a pheochromocytoma in some patients.

Desensitization does not account for all patients who are normotensive in the face of elevated serum levels of norepinephrine, because some such patients can still have hypertensive responses to norepinephrine. Secretion of epinephrine can have a hypotensive effect and may account, at least in part, for this phenomenon. Some patients are homozygous for certain polymorphisms of β2-adrenergic receptors that allow continued β2-adrenergic-mediated vasodilation, thus counteracting the pressor effects of circulating epinephrine and norepinephrine caused by stimulation of vascular α1-adrenergic receptors.

Cosecretion of DOPA may reduce blood pressure through a central nervous system action. Similarly, cosecretion of dopamine may directly dilate mesenteric and renal vessels and thus modulate the effects of norepinephrine.

Biochemical Testing for Pheochromocytoma

No single test is absolutely sensitive and specific for pheochromocytoma. Plasma-fractionated free metanephrines or urinary 24-hour metanephrines have a sensitivity of about 97%. Sensitivities of other tests are somewhat lower: urinary norepinephrine 93%, plasma norepinephrine 92%, urinary VMA 90%, plasma epinephrine 67%, urinary epinephrine 64%, and plasma dopamine 63%. However, some malignant tumors secrete only dopamine and no catecholamines and no metanephrines at all. Also, the determination of plasma catecholamines-metanephrine ratios can be of value in discriminating false-positive from true-positive results (see later). Therefore, assays for plasma catecholamines, dopamine, and serum chromogranin A are often warranted.

Pheochromocytomas are deadly tumors and missing the diagnosis can be disastrous, so screening tests must be very sensitive. The secretion of catecholamines can be paroxysmal, with low secretion rates between paroxysms. In contrast, the secretion of metanephrine or normetanephrine metabolites is relatively high and constant. Tumors secrete metanephrines in their unconjugated (free) form. Thus, plasma-fractionated free metanephrines is the single most sensitive screening tests for these tumors. Urinary 24-hour fractionated metanephrines has a similar sensitivity but is less convenient. Some rare tumors (usually malignant) have a defect in the conversion of dopamine to norepinephrine by DBH, such that serum dopamine levels are very high while catecholamines are normal or mildly elevated and metanephrines are totally normal. Additionally, some paragangliomas secrete no catecholamines or metanephrines but do secrete chromogranin A.

The establishment of normal reference ranges is problematic for catecholamines and metanephrines, since levels vary with sex, age, and medical conditions:

1. Sex—Women have lower plasma epinephrine and metanephrine levels than men; their urinary excretion of catecholamines and metanephrines is also lower.

2. Age—Children, especially boys, have somewhat higher levels of plasma epinephrine and metanephrine than do adults. Conversely, children's average 24-hour urine epinephrine and norepinephrine excretion rates are lower than those of adults and increase through childhood as weight increases. Therefore, children's 24-hour urine tests are best assessed by using ratios of catecholamines to creatinine and metanephrines to creatinine. In adults, plasma norepinephrine and normetanephrine levels increase with advancing age.

3. Medical conditions—On average, hospitalized patients and those with essential hypertension have higher levels of catecholamines and metanephrines (plasma and urine) than do matched nonhospitalized and normotensive individuals. Therefore, many laboratories have separate reference ranges for hypertensives and nonhypertensives.

Patients with illness, trauma, or sleep apnea have increased excretion of both catecholamines and metanephrines. Patients with renal failure on dialysis have elevated levels of plasma catecholamines (58%), plasma free metanephrines (25%), and plasma total (deconjugated) metanephrines (100%). Patients with partial renal insufficiency also have misleadingly elevated levels of plasma catecholamines (32%), plasma free metanephrines (26%), and plasma total metanephrines (50%). Thus, in patients with renal failure, the best screening test is plasma free metanephrines, but the test still lacks specificity when elevated. Serum chromogranin A levels are also elevated in renal insufficiency.

Misleading elevations of at least one metanephrine or catecholamine determination occur in 10% to 20% of tested individuals without pheochromocytoma. These elevations are typically less than 50% above the maximum normal and often normalize on retesting. Patients with pheochromocytomas usually have elevations of metanephrines or catecholamines that are more than three times normal. In one large series, a false-positive elevation in at least one test occurred in 22% and marked elevations in at least one test occurred in 3.5% of patients with no pheochromocytoma. False-positive test results were judged to have occurred from physiologic variation (33%), laboratory errors (29%), or drug interference (21%).

Plasma normetanephrines reflect disease activity in patients with secretory paragangliomas or metastases. Normal ranges for plasma metanephrines in children are different from those of adults and have been reported by Weise et al, 2002. Plasma normetanephrine levels typically increase with age; about 16% of older patients being evaluated for pheochromocytoma have levels above the published normal range for young adults (false positives); only 3% of young adults have false-positive plasma normetanephrine concentrations. Plasma concentrations of norepinephrine do not correlate with blood pressure. Stimulation tests are not recommended (see later).

Metanephrines and Catecholamines

Plasma-Fractionated Free Metanephrines

The most sensitive test for pheochromocytoma is an assay for plasma-fractionated (metanephrine and normetanephrine) free metanephrines. This assay is particularly useful when screening for a small pheochromocytoma in patients with established MEN 2 (metanephrine) or VHL disease (normetanephrine). For younger children, plasma testing is preferred to urine testing due to the relative ease of collection.

Normal references ranges for plasma-fractionated metanephrines vary by sex (children), age, and laboratory. For boys ages 5 to 17 years, the upper limit of normal (ULN) for plasma free metanephrine is ≤0.52 nmol/L and the ULN for plasma free normetanephrine is ≤0.53 nmol/L. For girls ages 5 to 17 years, the ULN for plasma free metanephrine is ≤0.37 nmol/L and the ULN for plasma free normetanephrine is ≤0.42 pmol/L. For adults, the reported ULN for plasma free metanephrine has ranged from 0.30 to 0.47 nmol/L and the reported ULN for plasma free normetanephrine has ranged from 0.60 to 1.1 nmol/L. In conventional units, the adult ULN reported by Quest Diagnostics Laboratory is ≤57 pg/mL for plasma free metanephrine and ≤148 pg/mL for plasma free normetanephrine.

In the United States, most reference laboratories assays for metanephrines use high-pressure liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS). This test is 97% sensitive and about 87% specific for pheochromocytoma in a referred patient population. MS/MS reduces drug interference that can be a problem with assays that employ HPLC with electrochemical detection (ECD). Metanephrine assays are more sensitive and specific for pheochromocytoma than plasma or urinary catecholamine determinations.

The 3% of affected patients with normal plasma-fractionated free metanephrines usually have very small tumors, nonsecreting tumors, or dopamine-secreting tumors such that they are not hypertensive. Since the test's specificity is much lower than its sensitivity, most patients with levels above the reference range do not harbor a tumor. This is particularly true when plasma levels are less than three times higher than the upper limit of the reference range. Conversely, it is extremely likely that a patient harbors a pheochromocytoma when the plasma metanephrine is above 236 pg/mL (1200 nmol/mL) or the plasma normetanephrine is above 400 pg/mL (2200 nmol/mL).

Normally, about 90% of circulating metanephrine and about 50% of circulating normetanephrine originate directly from the adrenal medulla. The term total metanephrines refers to both normetanephrine and metanephrine. There are two circulating forms of normetanephrine and metanephrines: free and sulfate-conjugated metanephrines. The free metanephrines produced in the adrenal medulla and paraganglia are sulfate conjugated by intestinal tissue; the sulfated form represents 97% of circulating metanephrines. Only 3% of total circulating metanephrine is free. Plasma metanephrine levels are sometimes measured after a deconjugation step, such that both free and conjugated metanephrines are measured; this assay is termed deconjugated metanephrines and reflects mostly the sulfate-conjugated species. The plasma free metanephrines assay is superior to the total (deconjugated) metanephrine assay.

In the United States, when plasma metanephrines are requested, most reference laboratories test for free (nondeconjugated) metanephrines. Most reference laboratories assay metanephrines using MS/MS, which avoids interference by drugs and foods. Blood specimens for plasma-fractionated free metanephrines can be collected at any time, but are best drawn after an overnight fast while the patient is seated and relaxed.

The sensitivity of the plasma free metanephrines is due to the tumor's continuous secretion of metanephrines. Catecholamines in secretory vesicles exist in a dynamic equilibrium with the surrounding cytoplasm, with catecholamine uptake into the vesicles being balanced by their leakage into the cytoplasm. In the cytoplasm, the enzyme COMT converts epinephrine to metanephrine and converts norepinephrine to normetanephrine. The catecholamine metabolites then leak out of the cell continuously to become free metanephrines. While catecholamines are secreted in bursts associated with exocytosis of neurosecretory vesicles, free metanephrines are produced continuously. This eliminates the need to catch a paroxysmal hypertensive event. Plasma free metanephrine levels are within the reference range in 75% of patients on dialysis and 74% of patients with renal insufficiency. In contrast, plasma deconjugated metanephrines are within the reference range in 0% of patients on dialysis and in 50% of patients with renal insufficiency.

Factors Causing Misleading Plasma Free Metanephrine Levels

Smoking can elevate plasma free metanephrine assays. The patient must not smoke for at least 4 hours before collection. Epinephrine-like drugs should be discontinued for at least 7 days before the test. Other drugs that can interfere with the plasma free metanephrine assay include local anesthetics, cocaine, lidocaine, halothane anesthesia, MAO inhibitors, and acetaminophen. Drug withdrawal and severe stress can also increase plasma free metanephrine levels. Misleading elevations in plasma free metanephrines occur in children (especially boys), renal failure, and stressful illness. Physical exercise raises plasma free metanephrine and normetanephrine by over 80%. Assumption of a supine resting position reduces plasma metanephrine by an average of 34% and reduces normetanephrine by 19%, compared to standing at rest. Coffee increases plasma normetanephrine by 20% and food increases plasma normetanephrine by 8%; but they have no effect upon metanephrine levels. Blood samples should ideally be drawn from an indwelling heparin-locked intravenous line while the patient is fasting and resting supine. Blood should be centrifuged immediately and stored at 4oC to improve stability.

In patients with adrenal pheochromocytoma, over 90% of circulating metanephrine originates from the tumor, while variable percentages of circulating normetanephrine originate from the tumor. Patients with elevated plasma metanephrine are likely to have an adrenal pheochromocytoma, since paragangliomas do not secrete epinephrine or metanephrine. Metastases from epinephrine-secreting pheochromocytomas may sometime continue to secrete epinephrine and metanephrine.

24-Hour Urine-Fractionated Metanephrines

This assay, which measures the sum of both conjugated and free urinary metanephrines, rivals plasma free metanephrines in sensitivity. In the United States, most reference laboratories employ tandem mass spectrometry (MS/MS), which eliminates interference by drugs and foods. Urinary metanephrines are rather stable compounds, so it is not necessary to collect the specimen with acid preservative. Conversely, acid preservative (used for collection of urinary catecholamines) does not adversely affect metanephrines. The disadvantages of 24-hour urine collections include: (1) the inconvenience to the patient; (2) the likelihood that there will be an error in the patient's collection or in the laboratory's handling of the specimen; (3) the inaccuracy for patients with renal failure. (See Appendix for normal reference ranges for 24-hour metanephrines.)

Like plasma-fractionated metanephrines, urinary metanephrines are much more sensitive than they are specific. Most patients with elevated levels of fractionated metanephrines do not harbor a pheochromocytoma if their levels are less than three times the upper limit of the reference range. Conversely, patients are very likely to have a pheochromocytoma if the 24-hour urine metanephrine excretion is above 600 μg/d (3.0 μmol/d) or normetanephrine excretion is above 1500 μg/d (8.2 μmol/d).

As with plasma metanephrines, patients with elevated urinary metanephrine are likely to harbor an adrenal pheochromocytoma, since paragangliomas do not secrete epinephrine or metanephrine.

Plasma-Fractionated Catecholamines

Misleading elevations in plasma catecholamines commonly occur from the stress of having the phlebotomy. Normal plasma levels of catecholamines are listed in the Appendix.

Although plasma metanephrines are more sensitive than plasma catecholamines for detecting a pheochromocytoma, plasma catecholamines are of value in helping distinguish true-positive from false-positive results. In normal individuals, about 100% of circulating epinephrine originates from the adrenal medulla, while over 90% of circulating norepinephrine originates from peripheral sympathetic synapses. In both normals and those with pheochromocytomas, plasma norepinephrine levels fluctuate with the degree of peripheral sympathetic activation and both epinephrine and norepinephrine levels can increase during pheochromocytoma paroxysms. In patients with pheochromocytomas, the tumor's production of metanephrine metabolites is rather constant and relatively unrelated to peripheral sympathetic activity or a tumor's paroxysmal catecholamine secretion. Patients with false-positive test results due to sympathetic activation tend to have the following pattern: a higher percentage increase of plasma norepinephrine above the upper limit of the reference range compared to plasma normetanephrine; a higher percentage increase of plasma epinephrine above the upper limit of the reference range compared to plasma metanephrine.

Plasma catecholamines are of limited value in patients on dialysis and in those with renal insufficiency. About 58% of dialysis patients have plasma catecholamines above the normal reference range; about 32% of renal insufficiency patients have catecholamines above the normal reference range.

Most assays for plasma catecholamines currently employ HPLC with ECD; assays using tandem mass spectrometry (MS/MS) have not become generally available.

Urine-Fractionated Catecholamines and Dopamine

Adult normal maximal urinary concentrations for catecholamines and their metabolites are listed in the Appendix. A single 24-hour urine specimen is collected for fractionated catecholamines, fractionated metanephrines, dopamine, and creatinine. The container is acidified with 10 to 25 mL of 6 N HCl for preservation of the catecholamines; the acid does not interfere with metanephrine and creatinine assays. The acid preservative may be omitted for children for safety reasons, in which case the specimen should be kept cold and processed immediately. The laboratory requisition form should request that assays for fractionated catecholamines, fractionated metanephrines, and creatinine be performed on the same specimen.

A single-void urine specimen may be collected on first morning void or following a paroxysm. No acid preservative is used on single-void specimens, because it dilutes the specimen and is not required. For single-void collections, patients are instructed to void and discard the urine immediately at the onset of a paroxysm and then collect the next voided urine. The laboratory requisition should request spot urine for total metanephrine (by HPLC and ECD) and creatinine concentrations. It is prudent to contact the laboratory technician and explain that the specimen is meant to be a single-void urine and not a 24-hour specimen or else the specimen may be rejected. Patients with pheochromocytomas generally excrete over 2.2 μg total metanephrine/mg creatinine.

Urinary dopamine determination is not a sensitive test for pheochromocytomas. However, in patients with established pheochromocytomas, a normal urine dopamine is fairly predictive of benignity, whereas elevated urine dopamine excretion is seen in both benign and malignant pheochromocytomas.

Serum Chromogranin A

Some tumors (mostly paragangliomas) fail to secrete catecholamines or metanephrines. Serum chromogranin A (CgA) is a useful test to diagnose and monitor such nonsecretory tumors. CgA may be determined by immunoradiometric assays. The serum CgA assay has become useful for the diagnosis of pheochromocytoma. However, CgA undergoes extensive tumor-specific cleavages so that only certain serum assays are useful for clinical diagnosis.

Serum CgA levels have a circadian rhythm in normal individuals, with lowest levels found at 8 am and higher levels in the afternoon and at 11 pm. CgA levels are not elevated in essential hypertension. CgA is also secreted from extra-adrenal sympathetic nerves. Serum CgA levels are elevated in the great majority of patients with pheochromocytomas. The serum levels of CgA correlate with tumor mass, making CgA a useful tumor marker. However, smaller tumors may not be diagnosed. Serum CgA levels tend to be particularly elevated in patients with metastatic pheochromocytoma.

Serum CgA can be elevated even in patients with biochemically silent tumors. In patients with normal renal function, serum CgA has a sensitivity of 83% to 90% and a specificity of 96% for diagnosis of these tumors. However, the usefulness of serum CgA levels is negated by any degree of renal failure because of its excretion by the kidneys; even mild azotemia causes serum levels to be elevated. However, in patients with normal renal function, a high serum level of CgA along with high urine or plasma catecholamines or metanephrines is virtually diagnostic of pheochromocytoma.

Since CgA is also cosecreted with gastrin, serum CgA levels are also elevated in conditions with elevated serum gastrin: atrophic gastritis, pernicious anemia, postvagotomy, gastrinoma, gastric carcinoma, carcinoid tumor, and small cell lung carcinoma. CgA levels are elevated in about 60% of patients taking proton pump inhibitors (PPIs), but not H2 blockers. Serum CgA levels rise variably after meals, so blood for CgA should be drawn after an overnight fast or repeated fasting if a nonfasting level is elevated. False-positive testing has also occurred in patients with inflammatory bowel disease, liver disease, hepatocellular carcinoma, prostate cancer, pituitary tumors, rheumatoid arthritis, and stress. False-positives have been reported to be due to heterophile antibody interference with the assay. Serum CgA levels can also be elevated without any discernable cause.

Suppression and Stimulation Testing

Glucagon stimulation testing is no longer used since it can cause dangerous hypertension.

Clonidine suppression test: This test may help distinguish patients with pheochromocytoma from normals with elevated normetanphrine levels. Clonidine is a central a 2-adrenergic blocker that suppresses the release of norepinephrine at sympathetic nerve synapses, thereby reducing circulating levels of norepinephrine and its metabolite, normetanephrine. In contrast, in patients with pheochromocytoma, most circulating normetanephrine is derived from continuous leakage from the tumor, such that clonidine is less able to suppress it. This test is most accurate when free normetanephrine is assayed, rather than norepinephrine.

To perform the clonidine suppression test, the patient must be fasting overnight and avoid smoking or interfering medications such as phenoxybenzamine, b-blockers, tricyclics and diuretics for at least 48 hours. An indwelling venous catheter is inserted, and the patient should remain recumbent. Thirty minutes later, blood is drawn for baseline plasma free normetanephrine. Clonidine is then given orally in a dose of 0.3 mg/kg; 3 hours afterward, blood is again drawn for plasma free normetanephrine.

In 1 study of 49 normals without pheochromocytoma, clonidine suppressed plasma normetanephrine levels more than 40% or to below 112 pg/mL in 100%. However, clonidine failed to suppress normetanephrine in 46 of 48 patients with pheochromocytoma. Despite the potential helpfulness of the clonidine suppression test, it cannot be completely relied upon. Unnecessary surgeries have been performed on the basis of misleading clonidine suppression testing.

Other Laboratory Tests

1. Urine VMA— Urinary VMA determinations have an overall diagnostic sensitivity for pheochromocytoma of only about 63% and do not improve the sensitivity or specificity of other tests for the diagnosis of pheochromocytoma. However, some centers have traditionally used a combination of 24-hour urinary VMA, metanephrine, and creatinine determinations with good results. VMA is stable for 5 days at room temperature; 6 N HCl is used to preserve urine specimens that are stored for longer than 5 days before analysis. Before urine collections for VMA testing, patients must avoid salicylates, caffeine, phenothiazines, and antihypertensive drugs for 72 hours. Coffee, tea, chocolate, bananas, and vanilla must also be avoided. Normal ranges for VMA vary by age (see Appendix).

2. Plasma renin activity— Levels of plasma renin activity are not typically suppressed in patients with pheochromocytomas because catecholamines stimulate renin release, and some tumors may secrete renin ectopically.

3. Other tests— Patients with pheochromocytoma are frequently found to have an increased white blood count with a high absolute neutrophil count. Counts as high as 23,600/μL have been reported. Marked eosinophilia may sometimes occur. Hyperglycemia is noted in about 35% of patients with pheochromocytoma, but frank diabetes mellitus is uncommon. The erythrocyte sedimentation rate is elevated in some patients. Hypercalcemia is common and may be caused by bone metastases or tumoral secretion of PTHrP. Hypocalcemia occurs rarely. Erythrocytosis sometimes occurs, usually due to volume contraction and rarely due to ectopic secretion of erythropoietin.

Factors that May Cause Misleading Biochemical Testing for Pheochromocytoma

Several different methods may be employed for assay of urine and plasma catecholamines and metanephrines. Each assay uses different methods and internal standards. Most assays for catecholamines now employ HPLC with ECD. Such assays can be affected by interference from a diverse range of drugs and foods. These substances cause unusual shapes in the peaks on the chromatogram. Not all of these assays are the same, and the potential for interference depends on the particular method employed. Therefore, it is best to check with the reference laboratory that runs the test or provides the test kit.

Drugs

(See Table 11–14)

Certain radiopaque contrast media, including those that contain meglumine acetrizoate or meglumine diatrizoate (eg, Renografin, Hypaque-M, Renovist, Cardiografin, Urografin, and Conray), can falsely lower urinary metanephrine determinations in some assays for up to 12 hours following administration. However, diatrizoate sodium is an intravenous contrast agent that does not cause such interference and should be requested if a CT scan must be performed prior to testing for metanephrines. Many other drugs cause interference in the older fluorometric assays for VMA and metanephrines. Tandem mass spectrometry for metanephrines virtually eliminates direct drug interference in the assay.

Foods

Even while using HPLC-ECD assay techniques, certain foods can cause misleading results in assays for catecholamines and metanephrines (see Table 11–16). Coffee (even if decaffeinated) contains substances that can be converted into a catechol metabolite (dihydrocaffeic acid) that may cause confusing peaks on HPLC. Caffeine inhibits the action of adenosine; one action of adenosine is to inhibit the release of catecholamines. Heavy caffeine consumption causes a persistent elevation in norepinephrine production and raises blood pressure an average of 4 mm Hg systolic. Bananas contain considerable amounts of tyrosine, which can be converted to dopamine by the central nervous system; dopamine is then converted to epinephrine and norepinephrine. Dietary peppers contain 3-methoxy-4-hydroxybenzylamine (MHBA), a compound that can interfere with the internal standard used in some assays for metanephrines.

Diseases

Any severe stress can elicit increased production of catecholamines and metanephrines. Urinary excretion of catecholamines and metanephrines is reduced in renal failure.

Differential Diagnosis of Pheochromocytoma

(Table 11–15)

Pheochromocytomas have such protean manifestations that many conditions enter into the differential diagnosis. Essential hypertension is extremely common, and it is not practical to screen for pheochromocytoma in all patients with elevated blood pressure. However, pheochromocytoma should enter the differential diagnosis for any hypertensive patient having blood pressures above 180 mm Hg systolic and for any hypertensive patient who has one of the following symptoms: headaches, palpitations, sweating episodes, or unexplained bouts of abdominal or chest pains.

Anxiety (panic) attacks begin abruptly and can be associated with tachycardia, tachypnea, and chest discomfort, symptoms that are commonly seen with pheochromocytomas. However, patients with panic attacks are more likely to have a precipitating social situation, tend to be exhausted for more than 2 hours following an attack, live in dread of the next attack, and often change their activities to avoid situations that might trigger anxiety.

Renal artery stenosis and renal parenchymal disease can cause increased secretion of renin resulting in severe hypertension. However, a detectable serum renin level does not exclude pheochromocytoma, because catecholamines can stimulate renin secretion and pheochromocytomas can secrete renin ectopically. Furthermore, large pheochromocytomas and paragangliomas arising near the renal hilum can occlude the renal artery, causing concomitant renovascular hypertension.

Hypogonadism can cause vasomotor instability in both women and men; attacks of flushing, sweating, and palpitations can mimic symptoms seen with pheochromocytoma. Factitious symptoms may be caused by surreptitious self-administration of various drugs such as epinephrine. Hyperthyroidism can cause heat intolerance, sweating, palpitations, and systolic hypertension with a widened pulse pressure. Carcinoid syndrome causes flushing during attacks but usually without pallor, hypertension, palpitations, or diaphoresis.

Obstructive sleep apnea can cause systemic hypertension; recurrent nocturnal hypoxia results in repeated episodes of stressful arousal that cause bursts of secretion of catecholamines, particularly epinephrine. Sleep apnea has been reported to cause misleading increases in the urinary excretion of catecholamines.

Patients with erythromelalgia can have episodic hypertension, but it is associated with flushing of the face and legs during the attack; patients with pheochromocytoma typically have facial pallor during attacks. With erythromelalgia, patients have painful erythema and swelling in the legs that is relieved by application of ice; such symptoms are not characteristic of pheochromocytoma.

Patients who have intermittent bizarre symptoms may have their blood pressure and pulse checked during a symptomatic episode with a home blood pressure meter or an ambulatory blood pressure monitor. Those who are normotensive during an attack are not likely to harbor a pheochromocytoma.

Pheochromocytomas often present with abdominal pain and vomiting. Such symptoms are similar to those of an intra-abdominal emergency, particularly in the presence of leukocytosis and fever, which can also be seen with pheochromocytomas. Abdominal pain usually prompts a CT scan of the abdomen, which generally shows the pheochromocytoma or paraganglioma. Even after detection on CT scan, pheochromocytomas and juxtarenal paragangliomas may be mistaken for renal carcinoma. Large left-sided pheochromocytomas are often mistaken for carcinoma of the tail of the pancreas.

Neuroblastoma is the most common extra-cranial solid malignancy of childhood. It is also the most common malignancy in infants under 18 months old. Neuroblastomas are derived from the embryonic neural crest of the peripheral sympathetic nervous system. They most often arise in the adrenal gland, but can also develop in sympathetic nerve ganglia near the cervical or thoracic vertebrae or in the pelvis. They metastasize to bones, lymph nodes, liver, and skin. Symptoms depend upon the age of the patient, site of origin, degree of metastatic involvement, and the systemic response to the tumor. Infants usually present with localized disease (Stage 1 or 2) or with a special disseminated pattern of disease (Stage 4S—infants with metastatic disease to liver and/or skin) associated with a favorable outcome. In contrast, most children over 1 year of age present with advanced disease (Stage 3 or 4). Unfavorable biologic features include amplification of myelomatosis viral-related oncogene, neuroblastoma (MYCN), deletion or loss of heterozygosity of chromosome 1p or 11q and gains at 17q. Favorable biologic features include hyperdiploidy and overexpression of the gene encoding the nerve growth factor receptor, tyrosine kinase A (TrkA). About 85% of affected children secrete excessive catecholamines—but rarely in sufficient amounts to cause symptomatic hypertension or the paroxysms typical of pheochromocytomas. Most neuroblastomas concentrate 123I-MIBG but they can be distinguished from pheochromocytomas and paragangliomas by clinical and histologic criteria.

Localization Studies for Pheochromocytoma

There are several available imaging modalities for pheochromocytoma and paraganglioma, each having unique sensitivity and specificity. There is no single imaging study that is 100% sensitive and specific. Generally, when a pheochromocytoma or paraganglioma is suspected, the initial diagnosis is best made biochemically. The initial localization scan is with CT or MRI of the abdomen and pelvis, which will detect about 95% of these tumors. However, since paragangliomas can arise in the chest, further scanning of the chest may be required. Diagnostic confirmation that the tumor is a pheochromocytoma or paraganglioma may be done with either 123I-MIBG or 18F-FDA positron emission tomography (PET) scanning; unfortunately, these scans are only 78% sensitive for these tumors. Scanning with 18F-FDG or 18F-FDA PET is more sensitive for detecting metastases than is 123I-MIBG.

Computed Tomography

(Figure 11–10)

After a pheochromocytoma has been diagnosed by clinical and biochemical criteria, hypertension must first be controlled (see later), because intravenous ionic contrast can precipitate a hypertensive crisis. The pheochromocytoma must then be localized. It is useful to perform an initial nonenhanced (without intravenous contrast) CT of the adrenals because the density of an adrenal tumor can be better approximated without intravenous contrast. An adrenal mass with a density of less than 10 Hounsfield units (HU) is unlikely to be a pheochromocytoma. CT scanning of the entire abdomen (from the diaphragm through the pelvis) is obtained with intravenous contrast-enhanced and delayed contrast-enhanced imaging. Thin-section (2-5 mm) cuts should be obtained through the adrenals with an adrenal protocol that specifically looks for a vascular tumor blush and determines rate of contrast washout. Pheochromocytomas tend to have a tumor blush and slower contrast washout than adrenocortical adenomas. Hypertensive crises have been provoked in pheochromocytoma patients receiving ionic intravenous contrast agents; this has prompted the tradition of initiating an alpha-blocking agent before the CT scan. However, nonionic intravenous contrast poses much less of threat. No increases in blood pressure or plasma catecholamines were noted in a series of 10 pheochromocytoma patients who received iohexol intravenous nonionic contrast. Glucagon should not be used during a CT because it may provoke a hypertensive crisis.

If no mass is discovered, 123I-MIBG imaging may be obtained or the CT scan may be extended into the chest in search of a paraganglioma—or both procedures may be employed. The great majority of pheochromocytomas are over 2 cm in diameter, well within the resolution capacity of the CT scan.

The overall sensitivity of CT scanning for an adrenal pheochromocytoma is about 90%—and over 95% for pheochromocytomas that are over 0.5 cm in diameter. However, CT scanning is less sensitive for the detection of small adrenal pheochromocytomas or adrenal medullary hyperplasia; this becomes an important issue in patients with MEN 2 or VHL disease. CT is also less sensitive for detecting extra-adrenal paragangliomas and early recurrent tumors in the adrenal surgical bed. CT will not detect small metastases or some metastases that strictly involve the bone marrow without osteoclastic activity. Metal surgical clips pose problem for CT scanning, causing distortion artifact and reducing the resolution of the scan.

Magnetic Resonance Imaging

MRI is useful in the diagnosis of adrenal pheochromocytomas, paragangliomas, and metastatic disease. It may be used with or without gadolinium contrast. Intravenous gadolinium contrast does not cause hypertensive crisis. MRI scanning with intravenous gadolinium contrast is also useful for patients with a known allergy to intravenous iodinated CT contrast agents. MRI is the scanning technique of choice in children and during pregnancy, because it involves no radiation exposure. Since MRI scanning delivers no radiation, it is preferred for serially scanning patients known to harbor a gene mutation predisposing them to PHEO/PGL.

MRI can help determine whether an adrenal mass is a pheochromocytoma when biochemical studies are inconclusive. On MRI T1-weighted images, pheochromocytomas have a dull signal (due to lack of fat cells), similar to kidney and muscle, distinguishing it from adrenal cortical adenomas, which contain fat and therefore have an intensely bright signal on T1-weighted images. The hypervascularity of pheochromocytomas makes them appear bright on MRI T2-weighted images, without signal loss on opposed phase imaging. However, other adrenal malignancies, adrenal adenomas, and hemorrhages can also appear bright on MRI T2-weighted images. Therefore, MRI scanning cannot definitively identify an adrenal mass as a pheochromocytoma. MRI of the abdomen has a sensitivity of about 95% for adrenal pheochromocytomas over 0.5 cm in diameter. Like CT scanning, MRI is less sensitive for the detection of extra-adrenal paragangliomas, metastatic disease, and recurrent small tumors in the adrenal surgical bed. MRI is helpful in visualizing paragangliomas that are intracardiac, juxtacardiac, or juxtavascular; MRI is particularly important for patients with paragangliomas adjacent to the vena cava or renal vein to detect vascular invasion. MRI is superior to CT in visualizing paragangliomas of the bladder wall. MRI can visualize some metastases to bone suspected on 123I-MIBG imaging or PET scanning. Another advantage of MRI scanning is that retained internal metallic surgical clips do not cause the distorting reflection artifacts that occur with CT scanning.

The disadvantages of MRI scanning include expense and its inability to crisply image lungs (due to movement artifact). Also, morbidly obese patients may not be able to fit into a standard helical MRI scanner; open MRI scanners can be used but are generally less sensitive. Claustrophobic patients require a sedative before the scan or an open MRI. Patients with internal pacemakers or defibrillators may not have MRI scans; nor may patients with implanted neural stimulators, cochlear implants, Swan-Ganz catheters, insulin pumps, cerebral aneurysm clips, ocular metallic foreign bodies, or retained metal shrapnel or bullets. Patients with retained surgical clips, artificial heart valves and joints may have MRI imaging; the spine may be imaged in patients with spinal hardware, but the imaging can be distorted.

Metaiodobenzylguanidine Scanning

(Figure 11–11 and Table 11–16)

MIBG is a guanidine derivative that resembles norepinephrine and is actively transported into adrenal medullary cells via the norepinephrine transporter system, selectively accumulating in neurosecretory granules. Unlike norepinephrine, MIBG has low affinity for catecholamine receptors and is not metabolized.

Scintigraphy using 123I-MIBG or 131I-MIBG is useful for determining whether an adrenal mass is a pheochromocytoma, for imaging occult paragangliomas, and for confirming whether a certain extra-adrenal mass is a paraganglioma or neuroblastoma. MIBG scanning is also useful for screening patients for metastases. MIBG uptake can often be seen in apparently nonfunctioning pheochromocytomas.

The isotope that is preferable for precise imaging is 123I-MIBG, because 123I emits γ radiation at lower energy (159 keV) than does 131I (364 keV). The lower-energy γ emissions allows crisper images with 123I-MIBG scanning as well as single photon emission computed tomography (SPECT). 123I-MIBG SPECT scanning is more sensitive than 123I-MIBG planar imaging for detecting small metastases and has the advantage of being able to do the scanning on the day following injection of the isotope. SPECT scanning with 123I-MIBG can be combined with CT to produce a three-dimensional fusion scan; the resultant combined images can help distinguish whether a given mass has 123I-MIBG uptake.

123I-MIBG is administered intravenously in doses of 3 mCi (children) to 10 mCi (adults), whereas 131I-MIBG is administered intravenously in doses of 0.5 to 1 mCi. 123I emits lower energy γ radiation and less heavy particle radiation over a shorter period than 131I, so 123I-MIBG scanning results in a somewhat lower absorbed radiation dose than 131I-MIBG scanning. However, most centers still use 131I-MIBG due to its longer half-life, lower expense, and better commercial availability.

123I-MIBG scanning has an overall sensitivity of 82% and a specificity of 82% for pheochromocytomas and paragangliomas combined. The sensitivity of 123I-MIBG scanning is 88% for primary adrenal pheochromocytomas and 67% for paragangliomas, with an overall sensitivity of 78% for primary PHEO/PGL tumors. The sensitivity of 123I-MIBG scanning for metastases is lower at only 57%. Scanning with 123I-MIBG is more sensitive for pheochromocytomas that are benign, unilateral, adrenal, capsule-invasive, and sporadic. Scanning with 123I-MIBG is less sensitive for bilateral, malignant, extra-adrenal, noninvasive, and MEN 2-related or VHL-related pheochromocytomas.

To block the thyroid's uptake of free radioiodine, saturated solution of potassium iodide, five drops orally three times daily, is given before the injection and daily for 4 days after 123I-MIBG and for 7 days after 131I-MIBG. Scanning is performed 24 to 48 hours after 123I-MIBG infusion and 48 to 72 hours after131I-MIBG infusion.

False-negative MIBG scans are seen in about 15% of cases of either benign or malignant pheochromocytoma. False-negative scans can occur in patients who have taken certain drugs (eg, tricyclic antidepressants or cyclobenzaprine) within 6 weeks. Other drugs that can cause false-negative scans when taken within 2 weeks include amphetamines, phenylpropanolamine, haloperidol, phenothiazines, thiothixene, reserpine, nasal decongestants, cocaine, and diet pills. Labetalol reduces MIBG uptake, but the scan can still be done, albeit with suboptimal sensitivity (Table 11–16). When plasma norepinephrine levels are over 500 pg/mL (3 nmol/L), cardiac visualization is reduced on 18F-dopamine PET scanning. This phenomenon is believed due to competitive inhibition of uptake-1 by high levels of circulating norepinephrine. Therefore, it is likely that very high endogenous norepinephrine levels may reduce the sensitivity of 123I-MIBG scanning as well as PET scanning that employs 18F-DA or 19F-DOPA because these compounds are transported into pheochromocytomas, paragangliomas, and their metastases by the same uptake mechanism.

False-positive MIBG scans occur infrequently. Following 123I-MIBG, some uptake in a normal adrenal medulla is seen in 32% to 75% of patients at 24 hours. Following 131I-MIBG, uptake in a normal adrenal medulla is seen in 16% of normals at 48 hours. Adrenal uptake is often asymmetric and can be misinterpreted as showing a tumor. MIBG has renal excretion, so the renal pelvis and bladder are usually visualized on scanning and must be distinguished from tumor. If a patient is being evaluated for a bladder mass (ie, to exclude a paraganglioma), a bladder catheter may be inserted and the bladder flushed with saline to distinguish tumor from renal excretion of isotope. Urine contamination with 123I-MIBG can also cause a false-positive scan. False-positive results have been reported with adrenal carcinomas and infections such as actinomycosis. The salivary glands are typically visualized since they are richly innervated. The heart, liver, and spleen normally take up some 123I-MIBG. Some isotope is excreted in the stool, and intracolonic collections can be mistaken for tumor. When there is doubt about whether an area of uptake is a tumor, scanning can be repeated the next day, preceded by a laxative if required.

Positron Emission Tomography

(Figure 11–12)

PET scanning can be performed shortly after the intravenous infusion of short-lived isotopes that are tagged to a compound that is preferentially absorbed by tumor tissue. These isotopes emit positrons (anti-matter) during their decay, causing positron-electron collisions that emit γ photons traveling in precisely opposite directions (180 degrees out of phase). In the PET scanner, sensitive gamma detectors surround the patient; simultaneous activation of two gamma detectors indicates that the source is located directly between them. Multiple such detections of this nature allow three-dimensional imaging of tumors and can accurately determine their location. Advanced scanners can perform PET and CT scanning simultaneously to produce particularly sensitive and accurate three-dimensional anatomic imaging.

PET scanning has certain advantages over MIBG scanning. PET scanning can be done almost immediately. This gives it some advantage over MIBG scanning, which must be delayed for 24 to 48 hours after the injection to allow dissipation of background radiation. PET scanning does not require pretreatment with iodine to protect the thyroid, as is necessary with MIBG scanning. However, PET scanning is very expensive. The isotope 18F has a half-life of just 2 hours and must be produced in a cyclotron, so 18F-FDG or 18F-FDA PET scanning is practical only at medical centers that have a cyclotron nearby.

1. PET scanning with 18F-FDG—Deoxyglucose (DG) is absorbed by tissues with active metabolism, including tumors. For PET scanning, DG is tagged with 18F to produce fluorodeoxyglucose, or 18F-FDG. This scan is widely available as a fusion scan with CT, 18F-FDG PET/CT. This scan's sensitivity is 88% for nonmetastatic pheochromocytoma/paraganglioma and 76% for metastatic pheochromocytoma/paraganglioma. The sensitivity of 18F-FDG-PET/CT is lower for indolent tumors and for patients who are diabetic or who are not fasting before the scan. 18F-FDG-PET localizes in other tissues with a high metabolic rate, including areas of inflammation, brown fat, shivering muscles, but such areas of PET uptake can be distinguished from tumors by the lack of a CT correlate. However, 18F-FDG-PET/CT detects other tumors besides pheochromocytoma/paraganglioma and is, therefore, less specific for pheochromocytoma/paraganglioma than is18F-FDA-PET or 123I-MIBG scanning.

2. PET scanning with 18F-FDA—PET scanning may also be performed using radioisotope-tagged dopamine: 6-[18F] fluorodopamine (18F-FDA-PET). This scan is more specific for paraganglioma and metastatic pheochromocytoma than is 18F-FDG-PET/CT, because dopamine is a substrate for the norepinephrine transporter in tumor tissue. The sensitivity of 18F-FDA-PET is 78% for nonmetastatic pheochromocytoma/paraganglioma and 76% for metastatic pheochromocytoma/paraganglioma. It is widely available and is generally more sensitive than 123I-MIBG scanning, particularly in patients who harbor VHL or MEN 2 germline mutations.

3. PET scanning with 18F-DOPA—PET scanning may be performed using radioisotope-tagged DOPA: 6-[18F]fluoro-l-dihydroxyphenylalanine (18F-DOPA). The sensitivity of 18F-DOPA-PET is about 81% for nonmetastatic PHEO/PGL and 45% for metastatic pheochromocytoma/paraganglioma. For SDHB-associated metastatic paraganglioma, its sensitivity is only 20%. This scan is not widely available and is not recommended because of its lack of sensitivity for metastatic pheochromocytoma or paraganglioma.

Somatostatin Receptor Imaging with 111Inoctreotide

Somatostatin receptors are cell surface, transmembrane, and G protein–coupled receptors, and there are five subtypes. About 70% of pheochromocytomas express somatostatin receptors, particularly types 2 and 4. Octreotide is a stable 8 amino acid analog of somatostatin with a high affinity for type 2 receptors. For imaging, octreotide is coupled with 111In-diaminetriaminepentacetate (DTPA). 111In has a half-life of 2.8 days and γ emissions of 173 keV and 247 keV. Scanning with 111In-labeled octreotide, known as somatostatin receptor imaging (SRI), has a sensitivity of only 25% for adrenal pheochromocytomas and juxtarenal paragangliomas. This low sensitivity is due to high uptake of 111In-octreotide by the kidneys as well as renal excretion. However, SRI detects 87% of pheochromocytoma metastases and is also a sensitive technique for detecting paragangliomas of the head and neck (chemodectomas). SRI also detects some metastases not visible on MIBG scanning, and vice versa. SRI has been reported to detect a cardiac paraganglioma that was not visible on MIBG scanning. When paragangliomas or metastases are suspected, SRI may be useful, particularly when MIBG scanning is negative.

111In-octreotide has physiologic uptake in the kidneys, thyroid, pituitary, salivary glands, gallbladder, bowels, spleen, liver, and mammary glands. Infection and recent surgery sites can also have misleading uptake of 111In-octreotide.

Ultrasound Imaging

On transabdominal ultrasound, an adrenal pheochromocytoma typically appears as a well-defined mass. Large pheochromocytomas tend to develop internal hemorrhagic necrotic cysts, making the tumor appear heterogenous. Transabdominal ultrasound is most sensitive in slender individuals, in whom 85% of adrenal pheochromocytomas can be visualized. However, ultrasound lacks specificity, such that a pheochromocytoma is not distinguishable from an adrenal adenoma or a mass in the superior pole of a kidney. Likewise, a left adrenal pheochromocytoma may be mistaken for a pancreatic tail tumor, and a right adrenal pheochromocytoma may be mistaken for a hepatic mass. Ultrasound may be used for initial imaging for pheochromocytomas in pregnant women, infants, and young children, although MRI is superior. Ultrasound is also useful for imaging and surveillance of neck paragangliomas. Ultrasound examinations have also been performed endoscopically, from the stomach and duodenum, with a longitudinal sector array, yielding sensitive detection of small adrenal pheochromocytomas, lymphangitic metastases, and local recurrences. For pelvic and bladder paragangliomas, pelvic transvaginal ultrasound is very helpful for tumor localization and surveillance.

Venous Sampling for Catecholamines

(See Figure 11–9)

Selective venous sampling for catecholamines is dangerous, since the required venography can provoke a pheochromocytoma crisis. Venous sampling can help distinguish whether a mass is a secretory pheochromocytoma or paraganglioma. However, venous sampling it is rarely required and seldom indicated.

Incidentally Discovered Adrenal Masses

Clinically inapparent adrenal nodules are commonly discovered incidentally on abdominal CT or MRI scans that are performed for unrelated reasons. (See “Computed Tomography,” earlier.) Such nodules are known as adrenal incidentalomas. The incidence of adrenal nodules is about 3% in middle-aged, rising to 10% in the elderly. Most such nodules are small, benign adrenal adenomas, with densities below 10 HU on noncontrast CT. However, pheochromocytomas can produce nonspecific symptoms of abdominal pain, nausea, and weight loss, for which CT scans may be performed. Pheochromocytomas account for about 4% of incidentally discovered adrenal masses. In the United States nearly half of the pheochromocytomas diagnosed during life are detected incidentally on an abdominal or chest CT scan performed for other reasons. Therefore, all patients with adrenal nodules, even normotensives, should be screened for pheochromocytoma with plasma-fractionated free metanephrines. A problem arises with metanephrines that are marginally elevated. Such patients with metanephrines that are one to two times higher than the reference range's ULN have about a 30% chance of harboring a pheochromocytoma. Those with metanephrines more than twice the ULN have a very high risk of having a pheochromocytoma. For apparently nonfunctioning adrenal nodules, it is generally reasonable to observe those that are under 3 cm in maximum diameter. Nonfunctioning nodules that are 3 to 5 cm in maximum diameter require especially close surveillance. Adrenal nodules that are over 5 cm in diameter are generally resected, except for obvious myelolipomas. When pheochromocytoma has been ruled out, patients with an adrenal nodule should be screened for hyperaldosteronism and Cushing syndrome.

Adrenal Percutaneous Fine-Needle Aspiration Biopsy

Most pheochromocytomas can be readily diagnosed on the basis of their clinical, biochemical, and radiologic presentation. Fine- needle aspiration biopsy (FNAB) is not usually required for the diagnosis of a pheochromocytoma. However, some pheochromocytomas are discovered incidentally on abdominal CT or ultrasound and may be clinically or biochemically silent. Although there may be a temptation to biopsy such masses, patients with a suspicious adrenal or retroperitoneal mass require testing for pheochromocytoma before any biopsy. There is a 70% risk of complications after percutaneous FNAB of pheochromocytomas and paragangliomas. Such complications include: increased difficulty in the tumor's resection (41%), severe hypertension (15%), hematoma (30%), severe pain (25%), and incorrect or inadequate biopsy (25%). FNAB cytology can be misinterpreted as a different primary malignancy or a metastasis from another malignancy; this potential for confusion is due to the fact that pheochromocytomas are rare tumors and have pleomorphic and hyperchromic nuclei. Large left-sided pheochromocytomas have been misdiagnosed as carcinoma of the tail of the pancreas based on CT scanning and biopsy. Percutaneous biopsy can also disrupt the pheochromocytoma capsule and cause seeding of the tumor within the peritoneum.

Medical Management of Pheochromocytoma and Paraganglioma

Patients need to be treated with oral antihypertensives and stabilized hemodynamically prior to surgery. Patients receiving increasing doses of antihypertensive medications should have daily measurements of blood pressure and pulse rate in the lying, sitting, and standing positions. Additionally, patients are taught to determine their own blood pressure and pulse rate during any paroxysmal symptoms. Most clinicians gradually increase antihypertensive medications over 2 or more weeks. However, prolonged preoperative preparation has not proven more effective for preventing intraoperative hypertension than are shorter preparation periods. Some hypertensive patients have been admitted emergently for hypertension control and hydration, stabilized, and operated on successfully with intravenous infusion of a vasodilator drug (eg, nicardipine, nitroprusside, nitroglycerin; see discussed later). Ideally, the blood pressure should be reduced to an average of 130/85 mm Hg or less prior to surgery, while avoiding symptomatic orthostasis.

Alpha-Adrenergic Blockers

Alpha-adrenergic blockers have historically been used for most patients with pheochromocytoma in preparation for surgical resection. Patients who are normotensive are also usually treated (carefully) preoperatively. Phenoxybenzamine (10-mg capsules) is an oral nonselective alpha blocker that is the most commonly used alpha-blocking agent. It has a long half-life of about 24 hours. Patients with mild hypertension may be given phenoxybenzamine at a starting dosage of 10 mg once daily, while those with more severe hypertension may receive a starting dosage of 10 mg twice daily. The dose of phenoxybenzamine may be increased by 10 mg every 2 days until the blood pressure falls to an average of 130/85 mm Hg sitting or until symptomatic orthostatic hypotension occurs. Patients who have been normotensive between paroxysms are particularly prone to develop hypotension with phenoxybenzamine. Phenoxybenzamine does not block the synthesis of catecholamines; in fact, the synthesis of catecholamines and metanephrines tends to increase during alpha blockade. Therapy with phenoxybenzamine increases the heart rate but decreases the frequency of ventricular arrhythmias. Patients are encouraged to hydrate themselves well. Patients must be monitored daily for symptomatic orthostatic hypotension. Certain adverse effects are common, including dry mouth, headache, diplopia, inhibition of ejaculation, and nasal congestion. Nasal decongestants should not be used if urinary catecholamine determinations or 123I-MIBG scanning is planned, but antihistamines are acceptable. Phenoxybenzamine is not well tolerated as chronic therapy for hypertension in patients with unresectable or metastatic pheochromocytoma, and such patients are better treated with calcium channel blockers (see later), sometimes together with low-dose phenoxybenzamine.

Phenoxybenzamine crosses the placenta and accumulates to levels that are 60% higher in the fetus than in the maternal circulation; this can cause hypotension and respiratory depression in the newborn for several days following birth. Most patients require 30 to 60 mg/d, but the dosage is sometimes escalated to as high as 140 mg/d. Excessive alpha blockade with phenoxybenzamine is undesirable because it worsens postoperative hypotension. Furthermore, excessive alpha blockade may deny a critical surgical indicator (ie, a drop in blood pressure after complete resection of the tumor and aggravation of hypertension during palpation of the abdomen in case of multiple tumors or metastases).

Doxazosin is another alpha blocker with a half-life of about 22 hours. It is effective in the medical management of pheochromocytomas when given orally in doses of 2 to 16 mg daily. In one series, there was no difference in hemodynamic instability during surgery in patients pretreated with doxazosin versus phenoxybenzamine. Alternatively, prazosin is a short-acting selective alpha blocker with a half-life of about 3 hours. It appears to cause less reflex tachycardia and less postoperative hypotension. With chronic use, it has been reported to cause less ejaculatory disturbance in men, compared to phenoxybenzamine. The starting dose of prazosin is 0.5 mg/d, increasing up to 10 mg twice or three times daily, if necessary.

Calcium Channel Blockers

Calcium channel blockers are excellent antihypertensive agents for patients with pheochromocytomas. Patients tend to tolerate calcium channel blockers better than alpha blockers. Patients who are normotensive between paroxysms are less likely to become hypotensive with calcium channel blockers compared to alpha blockers. Patients with angina from coronary vasospasm are also best treated with calcium channel blockers. Perioperative fluid requirements have been lower among patients who were pretreated with calcium channel blockers instead of alpha blockers. In a French series, 70 patients with pheochromocytoma were successfully prepared for surgery using oral calcium channel blockers (usually nicardipine). Nicardipine may be given in doses of 20 to 40 mg orally every 8 hours; nicardipine is also available as a sustained-release preparation that may be given in doses of 30 to 60 mg orally every 12 hours.

Nifedipine is a calcium channel blocker that is administered as a slow-release preparation in doses of 30 to 60 mg orally once or twice daily. For hypertensive paroxysms, nifedipine 10 mg (chewed pierced capsule) is usually a fast and effective treatment. Chewed nifedipine is generally safe for use by patients with pheochromocytoma, who may self-administer the drug at home during paroxysms but only with close blood pressure monitoring. In one small study, nifedipine therapy appeared to improve the uptake of MIBG into pheochromocytomas in four of eight patients at scanning doses. It is possible that nifedipine might reduce the growth of pheochromocytomas and metastases, because in vitro nifedipine added to cultured pheochromocytoma cells reduces their mitotic index and proliferation. The effect of nifedipine on pheochromocytoma tumor growth in vivo has not been studied. Amlodipine may also be used for patients with pheochromocytoma in doses of 10 to 20 mg daily.

Other calcium channel blockers are reported to be less effective for patients with pheochromocytoma. Verapamil has been used in a sustained-release preparation, but has been reported to be associated with postoperative pulmonary edema after pheochromocytoma resection. Diltiazem has been reported to provide inadequate intraoperative blood pressure control.

Intravenous calcium channel blockers are useful for hypertensive crisis, particularly during surgery. Nicardipine and clevidipine are both available as intravenous preparations. (See “Surgical Management of Pheochromocytoma and Paraganglioma” later.)

Angiotensin-Converting Enzyme Inhibitors

ACE inhibitors have successfully treated hypertension in patients with pheochromocytomas but not as the sole agent. Angiotensin receptor blockers have also been successfully added to multidrug antihypertensive therapy. Catecholamines stimulate renin production. In turn, renin stimulates the production of angiotensin I, which is converted by ACE to angiotensin II; this can be blocked by ACE inhibitors. Furthermore, pheochromocytomas have been demonstrated to have angiotensin II–binding sites. ACE inhibitors are contraindicated in pregnancy, because their use in the second and third trimesters has been associated with fetal malformations, including skull hypoplasia, renal failure, limb and craniofacial deformation, lung hypoplasia, intrauterine growth retardation, patent ductus arteriosus, and death.

Beta-Adrenergic Blockers

These agents are generally not prescribed for patients with pheochromocytomas until treatment has been started with antihypertensive medications such as α-adrenergic blockers or calcium channel blockers. Beta-adrenergic blockade should then be used for treatment of β-adrenergic symptoms such as flushing, pounding heart, or tachycardia. It is important to institute alpha blockade first, because blocking vasodilating β2 receptors without also blocking vasoconstricting α1 receptors can lead to hypertensive crisis if serum norepinephrine levels are high.

Nonselective beta blockers block both β1- and β2-adrenergic receptors. The inhibition of vasodilating arterial β2 receptors causes unopposed vasoconstrictive α-adrenergic stimulation that aggravates hypertension. Therefore, nonselective beta blockers should ordinarily not be administered to patients with pheochromocytoma or paraganglioma. Nonselective beta blockers include: nadolol, pindolol, propranolol, and timolol. Labetalol and carvedilol are different nonselective β blockers that additionally block α1 receptors. Labetalol has been used to treat patients with pheochromocytoma; however, it can initially aggravate hypertension, produce false elevations of catecholamines in some assays, and reduce MIBG uptake.

Selective beta blockers specifically block β1-adrenergic receptors at low doses. This leads to a rather selective reduction in heart rate without unopposed alpha receptor dependent hypertension. However, at higher doses, these beta blockers also block β2-adrenergic receptors and can cause a paradoxical worsening of hypertension. Selective beta blockers include: atenolol, betaxolol, bisoprolol, nebivolol, esmolol, and metoprolol. Atenolol has a half-life of only 6 hours, so it does not produce satisfactory 24-hour blockade. Nebivolol has vasodilating activity through enhancement of nitric oxide release. Esmolol is the preferred intravenous preparation. Extended-release metoprolol (metoprolol ER) is the preferred oral preparation.

Metyrosine (α-Methylparatyrosine)

Metyrosine inhibits the enzyme tyrosine hydroxylase, which catalyzes the first reaction in catecholamine biosynthesis. Because of its potential side effects, it is usually used only to treat hypertension in patients with metastatic pheochromocytoma. Metyrosine is administered orally as 250-mg capsules, beginning with one every 6 hours; the dose is titrated upward every 3 to 4 days according to blood pressure response and side effects. Most patients can tolerate 2 g/d, but higher doses usually cause side effects. The maximum dosage is 4 g/d. Catecholamine excretion is usually reduced by 35% to 80%. Preoperative treatment with metyrosine tends to reduce intraoperative hypertension and arrhythmias; however, postoperative hypotension is likely to be more severe for several days. Side effects of metyrosine include sedation, psychiatric disturbance, extrapyramidal symptoms, and potentiation of sedatives and phenothiazines. Crystalluria and urolithiasis can occur, so adequate hydration is mandatory. Metyrosine does not inhibit MIBG uptake by the tumor, allowing concurrent 123I-MIBG scanning or treatment with high-dose 131I-MIBG.

Octreotide

Octreotide has not been formally studied or approved for use in patients with pheochromocytoma. However, octreotide (100 μg subcutaneously three times daily), has been reported to reduce hypertensive episodes and catecholamine excretion in a man with pheochromocytoma whose hypertensive paroxysms were uncontrolled using other means. Octreotide therapy has been observed to reduce bone pain in a woman with a malignant paraganglioma whose skeletal metastases were avid for 111In-labeled octreotide. Octreotide therapy is usually begun at a dose of 50 to 100 μg injected subcutaneously every 8 hours. Side effects are common and may include nausea, vomiting, abdominal pain, and dizziness. If the drug is tolerated, the dose can be titrated upward to a maximum of 1500 μg daily. Octreotide LAR can be given as subcutaneous injections in doses of 10 to 30 mg every 4 weeks.

Activities to Avoid

Vigorous exercise, particularly involving bending or heavy lifting, can aggravate hypertension in some individuals with pheochromocytoma, so mild exertion or rest is best during preparation for surgery. Emotional stress can provoke hypertensive attacks, so arguments and stressful situations are best avoided.

Foods to Avoid

Tyramine is a precursor to catecholamines and intravenous tyramine causes hypertension in most patients with pheochromocytoma. While dietary tyramine has not been studied in patients with pheochromocytoma, it is known that dietary tyramine can provoke hypertensive crisis in patients taking MAO inhibitor antidepressants. Therefore, although strict dietary precautions are not required, it is reasonable for patients with a known pheochromocytoma to avoid consuming large amounts of foods with high tyramine content during preparation for surgery such as red wine, tap beers, aged dairy products, aged meats, fermented or pickled fish, liver, protein extracts, overripe fruit, soybeans, tofu, fava bean pods, bean pastes, brewer's yeast pills, marmite, and vegemite.

Surgical Management of Pheochromocytoma and Paraganglioma

Perioperative Preparation

Prior to surgery, patients should be reasonably normotensive on medication, with an average blood pressure of 130/85 mm Hg or less, without symptomatic orthostasis (see earlier). They should also be well hydrated. It is ideal for patients to be admitted for administration of intravenous fluids at least 1 day prior to surgery. Patients may predonate blood for autologous transfusion. The transfusion of two units of blood within 12 hours before surgery reduces the risk of postoperative hypotension. Blood pressure must be monitored continuously during surgery. This requires placement of an arterial line, preferably in a large artery that is not prone to spasm (eg, femoral artery). A central venous pressure line helps determine the volume of fluid replacement. For certain high-risk patients with congestive heart failure or coronary artery disease, a pulmonary artery (Swan-Ganz) line may be inserted preoperatively to further optimize fluid replacement. Constant electrocardiographic monitoring is mandatory. Severe hypertension can occur—even in fully blocked patients—during bladder catheterization, intubation, or surgical incision. During laparoscopic surgery, catecholamine release is typically stimulated by pneumoperitoneum and by tumor manipulation. However, laparoscopic procedures cause less fluctuation of catecholamine levels and blood pressure than do open surgeries. All antihypertensive medications (see later) that might be required should be available and should be in the operating room well in advance.

Arterial embolization of the tumor can be performed immediately prior to surgery. This may be beneficial to the surgeon, particularly for the open resection of very large paragangliomas that tend to be extremely vascular and difficult to resect, due to blood loss and venous oozing. Embolization of neck paragangliomas is an established intervention. Secretory paragangliomas can also be embolized preoperatively. An experienced interventional radiologist must perform such embolizations with full monitoring and an anesthesia team in attendance.

The major problem during surgery for pheochromocytoma is hemodynamic instability. Serious blood pressure variations are more common in patients whose blood pressure has not been adequately pretreated. Intraoperative hemodynamic instability is also more common in patients with higher plasma norepinephrine levels and larger tumor size.

Antihypertensive and Antiarrhythmic Drugs

1. Calcium channel blockers—These are effective therapies for intraoperative hypertension. They can cause reflex tachycardia that can be controlled with intravenous beta blockers (eg, esmolol). Nicardipine is administered as an intravenous infusion, starting at a dose of 5 mg/h and increasing by 2.5 mg/h every 5 to 15 minutes up to 15 mg/h. Nicardipine was successfully used as the sole intraoperative vasodilating agent in one French series of 70 patients and in another series of 19 patients. Its half-life is 9 hours. Clevidipine has a shorter half-life of 1 to 15 minutes. It is available for intravenous infusion at a dose of 1 to 2 mg/h, doubling the dose after 90 seconds, then increasing in smaller increments at longer intervals (5-10 minutes) up to 4 to 6 mg/h or a maximum of 16 mg/h.

2. Phentolamine—It is a parenteral α-adrenergic blocker that has a short half-life of 19 minutes. It can be given intravenously in bolus doses, starting with 5 mg (children, 1-3 mg) and repeating in doses of 5 to 15 mg as needed for blood pressure control. Phentolamine may also be given by intravenous infusion at a rate of 0.5 to 1 mg/min. Side effects include hypotension, tachycardia, cardiac arrhythmias, nasal stuffiness, nausea, and vomiting.

3. Nitroprusside—It is given by intravenous infusion and is an effective drug for managing hypertensive episodes; advantages include widespread familiarity with its use and its short half-life of 2 minutes. Nitroprusside is initiated at 0.25 to 0.3 μg/kg/min and titrated for the desired effect. The maximum infusion rate is 10 μg/kg/min for 10 minutes. High infusion rates should not be given for prolonged periods; long-duration (over 6 hours) nitroprusside infusion rates above 2 μg/kg/min cause cyanide accumulation and toxicity. Cyanide toxicity causes metabolic acidosis and an increase in venous oxygen saturation (> 90%) in severe cases. If cyanide toxicity is suspected, the nitroprusside infusion must be stopped or slowed. In the United States, there are two different cyanide antidote kits available. (1) The conventional kit contains amyl nitrite, sodium nitrite, and thiosulfate. Administer an amyl nitrite crushed ampule at the end of the endotracheal tube or under the patient's nose and give 10 mL 3% sodium nitrite intravenously. Also administer 25% sodium thiosulfate solution (50 mL) intravenously. (2) Additionally, hydroxocobalamin (Cyanokit) is available for intravenous administration at a dose of 5 g (children, 70 mg/kg). Coadministration of sodium thiosulfate (1 g/100 mg nitroprusside) prevents cyanide accumulation. Nitroprusside must be administered cautiously, since it can cause precipitous and profound hypotension, resulting in irreversible ischemic injuries.

4. Nitroglycerin—It is given by intravenous infusion and is effective therapy for perioperative hypertension. Nitroglycerin infusions are initiated at 5 μg/min and increased by 5 μg/min every 3 to 5 minutes until target blood pressure is achieved or a dose of 20 μg/min is reached; if the response has been insufficient, the dose can be increased by 10 to 20 μg/min every 5 minutes to a maximum of 100 μg/min. Because nitroglycerin adheres to polyvinyl chloride tubing, non-PVC infusion sets must be used. Nitroglycerin infusions can cause headache and hypotension. Methemoglobinemia has occurred during prolonged high-dose infusions and is manifested by cyanosis in the presence of a normal arterial pO2. The therapy for methemoglobinemia consists of immediately stopping the nitroglycerin and giving methylene blue, 1 to 2 mg/kg intravenously.

5. Magnesium sulfate—It is given intravenously in a bolus of 4 g over 15 minutes and has been reported to be effective in managing hypertension during resection of a pheochromocytoma during pregnancy.

6. Lidocaine—It may be used to treat cardiac ventricular arrhythmias. In adults, lidocaine is administered with a loading dose of 150 to 200 mg over about 15 minutes, or as a series of smaller boluses. This is followed by a maintenance infusion of 2 to 4 mg/min in order to achieve a therapeutic plasma level of 2 to 6 μg/mL.

7. Beta blockers—Atrial tachyarrhythmias may be treated with intravenous atenolol in 1-mg boluses or by constant intravenous infusion of esmolol, a short-acting beta blocker. Esmolol is given as an initial dose of 500 μg/kg intravenously over 1 minute, then continued at 50 μg/kg/min. If required, the infusion rate may be increased by 50 μg/kg/min every 4 minutes.

8. Drugs to avoid—Atropine should not be used as preoperative medication for patients with pheochromocytomas because it can precipitate arrhythmias and severe hypertension. Metoclopramide and glucagon can also precipitate a hypertensive crisis. MAO inhibitor antidepressants can provoke hypertensive crisis by blocking the metabolism of catecholamines. Other medications that can elicit hypertensive crisis include decongestants (eg, pseudoephedrine), epinephrine, amphetamines and amphetamine derivatives, and cocaine.

   Labetalol is not recommended for preoperative or intraoperative management of pheochromocytomas because it aggravates postresection hypotension as a consequence of its long half-life. It can also paradoxically initially aggravate hypertension, because its beta-blocking effect may occur initially, allowing a brief period of unopposed α-receptor stimulation. Labetalol also inhibits MIBG uptake and causes misleading elevations in catecholamine determinations in certain assays. Diazoxide is ineffective against hypertension caused by pheochromocytoma.

Anesthesia

Anesthetic agents such as intravenous propofol, enflurane, isoflurane, sufentanil, alfentanil, and nitrous oxide appear to be safe and effective. Atropine should not be used. Muscle relaxants with the least hypertensive effect should be employed (eg, vecuronium). Intraoperative hypertension can be managed by increasing the depth of anesthesia and by intravenous vasodilators for blood pressures over 160/90 mm Hg. Serum catecholamine levels drop sharply after adrenal vein ligation and profound hypotension can occur suddenly after resection of a pheochromocytoma. Therefore, it is prudent to stop the vasodilator infusion just prior to adrenal vein ligation.

Operative Management

Perioperative mortality is about 2.4% overall, but morbidity rates of up to 24% have been reported. Surgical complications do occur and include splenectomy, which is more common with open abdominal exploration than with laparoscopic surgery. Reported surgical complication rates have been higher in patients with severe hypertension and in patients having reoperations. Surgical morbidity and mortality risks can be minimized by adequate preoperative preparation, accurate tumor localization, and meticulous intraoperative care.

1. Laparoscopy—Most pheochromocytomas can be resected laparoscopically, which has become the procedure of choice for removing most adrenal neoplasms that are under 6 cm in diameter. Adrenal laparoscopic surgery is usually performed through 4 subcostal ports of 10 to 12 mm. Laparoscopic surgery is widely used now that preoperative localization of the tumor is possible. However, tumors that are invasive or over 6 cm in diameter are more difficult to resect laparoscopically and may require open surgery. For larger pheochromocytomas, a lateral laparoscopic approach can be used, because it affords greater opportunity to explore the abdomen and inspect the liver for metastases. For patients with small adrenal pheochromocytomas and for those who have had prior abdominal surgery, a posterior laparoscopic approach may be preferred.

   The laparoscope allows unsurpassed magnified views of the pheochromocytoma and its vasculature. Pheochromocytomas are bagged to reduce the risk of fragmentation and spread of tumor cells within the peritoneum or at the port site. Larger tumors can be removed through laparoscopic incisions that can be widened for the surgeon's hand (laparoscopic-assisted adrenalectomy). With laparoscopic surgery, hypotensive episodes are less frequent and less severe. Laparoscopic adrenalectomy has other advantages also compared with open adrenalectomy: less postoperative pain, faster return to oral foods, and shorter hospital stays (median 3 days vs 7 days for the open approach). This approach is the least invasive for the patient, who can usually begin eating and ambulating the next day. The laparoscopic approach may be used during pregnancy. The technique has also been used successfully for certain extra-adrenal paragangliomas. Surgical mortality is under 3% at referral centers.

2. Needlescopic adrenalectomy—This procedure uses three subcostal ports of 3 mm, with a larger umbilical port for tumor removal. In one series of 15 patients, this technique reduced surgical times and recovery time compared with the standard laparoscopic approach. However, more extensive experience with this technique is required.

3. Adrenal cortex-sparing surgery—All patients undergoing bilateral total adrenalectomies require life-long glucocorticoid and mineralocorticoid hormone replacement. To avoid adrenal insufficiency, patients with benign familial or bilateral pheochromocytomas have had successful selective laparoscopic resection of small pheochromocytomas, sparing the adrenal cortex. Such adrenal-sparing surgery has unfortunately resulted in a pheochromocytoma recurrence rate of about 24%.

4. Open laparotomy—Open laparotomy is indicated for patients with particularly large pheochromocytomas or paragangliomas, or for those with intra-abdominal metastases that require debulking. Large vascular paragangliomas can be considered for preoperative arterial embolization, but its efficacy is uncertain. An open anterior midline or subcostal approach usually yields adequate exposure. For patients with paragangliomas of the urinary bladder, a partial cystectomy can sometimes be curative. Other patients with larger bladder paragangliomas require a total cystectomy and construction of a diverting ureteroenterostomy if the tumor has not been fully resected. For patients with a curative total cystectomy, construction of a new ileal neobladder is possible.

Therapy for Shock Occurring after Pheochromocytoma Resection

Severe shock and cardiovascular collapse can occur immediately following ligation of the adrenal vein during resection of a pheochromocytoma, particularly in patients having norepinephrine-secreting tumors. Such hypotension may be due to desensitization of α1-adrenergic receptors, persistence of antihypertensives, and low plasma volume. Preoperative preparation with calcium channel blockers or alpha blockade plus intravenous hydration or blood transfusions reduces the risk of shock. Intravenous antihypertensives are held just prior to ligation of the adrenal vein. Treatment of shock consists of large volumes of intravenous saline or colloid. Intravenous norepinephrine is sometimes required in very high doses.

Intravenous Dextrose

Immediately following removal of a pheochromocytoma, intravenous 5% dextrose should be infused at a constant rate of about 100 mL/h to prevent the postoperative hypoglycemia that is otherwise frequently encountered.

Pregnancy and Pheochromocytoma

Pheochromocytomas occur in about 1 in every 50,000 pregnancies and are unrecognized antepartum in about 50% of cases. Such unsuspected pheochromocytomas result in a maternal mortality of 40% and a fetal mortality of 56%. However, if the diagnosis is made antepartum, the mortality is much lower. Hypertension is often misdiagnosed as eclampsia. Hypertensive crisis usually occurs during labor and can be associated with cardiac arrhythmias or pulmonary edema. Although maternal catecholamines do not cross the placenta, maternal hypertensive crisis is very dangerous for the fetus, causing uteroplacental insufficiency and fetal death.

Pregnant hypertensive patients are often treated with methyldopa that can cause false-positive testing for catecholamines by older fluorometric methodologies, but not by HPLC. Methyldopa does not cause interference with plasma or urine metanephrine measurements performed with tandem mass spectrometry. The localization of a pheochromocytoma in pregnancy is best done with MRI.

As soon as a pheochromocytoma is diagnosed, alpha blockade is commenced. Phenoxybenzamine is usually used. However, phenoxybenzamine crosses the placenta and accumulates in the fetus. After 26 days of maternal phenoxybenzamine therapy, cord blood levels in the newborn are 60% higher than the mother's serum levels. Therefore, some perinatal depression and hypotension may occur in newborns of mothers receiving phenoxybenzamine. For maternal treatment near term, a short-acting selective alpha blocker (eg, prazosin) would have an obvious theoretical advantage over long-acting alpha blockers; chronic use increases the risk of fetal demise. The starting dose of prazosin is 0.5 mg/d orally, increasing up to 10 mg orally twice daily if necessary.

There has been little experience with the use of calcium channel blockers to treat hypertension in pregnant women with pheochromocytoma. However, calcium channel blockers can be safely used during pregnancy and are not teratogenic in the first trimester. Therefore, nifedipine or nicardipine may be used to supplement or replace alpha blockade as needed.

If possible, beta blockade should not be used at all during pregnancy. Propranolol crosses the placenta and can cause intrauterine growth restriction. Newborns of mothers taking propranolol at delivery exhibit bradycardia, respiratory depression, and hypoglycemia. Therefore, during cesarean delivery, serious atrial tachyarrhythmias should be controlled by a short infusion of esmolol, a beta blocker with a very short half-life.

During the first 6 months of pregnancy, it is often possible to treat a woman with alpha blockade, followed by laparoscopic resection of the tumor. Although the fetus usually survives, spontaneous abortion is common despite a successful resection of the tumor. If a pheochromocytoma is not discovered until the last trimester, treatment consists of alpha blockade followed by elective cesarean delivery as early as feasible. Intravenous magnesium sulfate is a useful antihypertensive during surgery. Intravenous calcium channel blockers may be used to treat patients with hypertensive crisis caused by pheochromocytoma in pregnancy. The tumor is resected after the cesarean delivery. In the presence of an active pheochromocytoma, vaginal delivery should never be allowed, since life-threatening hypertensive crisis will predictably occur.

Pathology of Pheochromocytoma and Paraganglioma

On histopathology, pheochromocytomas are extremely vascular tumors with neurosecretory granules. Central necrosis is often present. The cells may be arranged in nests (zellballen pattern), anastomosing cords (trabecular pattern), or a combination of both. Cells vary in size with pleomorphic and eccentric nuclei that are often large and bizarre in appearance. The cells exhibit immunofluorescence staining for CgA and synaptophysin.

No single characteristic of pheochromocytoma or paraganglioma can determine whether a given tumor is malignant. Therefore, the definition of malignancy is based upon whether metastases are present. Metastases must be distinguished from additional paragangliomas by their location (liver, lung, bone) where sympathetic paraganglia are rare. Metastases must also be distinguished from intraperitoneal seeding, a phenomenon known as pheochromocytomatosis. Metastases can vary in virulence from relatively indolent to extremely aggressive (see discussion on malignant pheochromocytoma later).

Overall, about 26% of these tumors arise in patients with identifiable germline mutations. Individuals with no known family history of these tumors have about a 17% risk of harboring a known germline mutation. About 18% of cases develop in children. The earlier a tumor presents, the more likely that individual harbors a germline mutation. (See discussion on genetics of pheochromocytoma and paraganglioma, earlier.)

Adrenal pheochromocytomas and paragangliomas appear very similar on microscopy. Paragangliomas are often large and arise near the adrenal, making the distinction particularly difficult based upon preoperative localization scans. But it is important to distinguish these two tumors because paragangliomas are more likely to metastasize. One way to distinguish these tumors preoperatively is to evaluate their secretions. Tumors that secrete epinephrine (or its metabolite, metanephrine) are predictably adrenal pheochromocytoma. However, tumors that secrete strictly norepinephrine (or its metabolite normetanephrine) may be either pheochromocytoma or paraganglioma. Intraoperatively, the surgeon may be able to identify the adrenal gland as separate from the tumor. On pathology, it is often possible to visualize the adrenal cortex lying in close proximity to the pheochromocytoma or even arising out of the adrenal medulla. An intact adrenal gland may be included in the surgical specimen, indicating that the tumor was a juxta-adrenal paraganglioma. On microscopy, paragangliomas may have visible nerve ganglia.

Composite pheochromocytomas are rare tumors that exhibit histopathologic features of both pheochromocytoma and neuroblastoma. Such tumors have generally not recurred and have not exhibited N-myc amplification, which distinguishes them from typical neuroblastomas. Therefore, composite pheochtomoctyomas are considered to be a histological variant of pheochromocytomas.

Metastatic Pheochromocytoma and Paraganglioma

(Table 11–17)

No pheochromocytoma or paraganglioma should be labeled benign. Histopathology cannot reliably determine whether a given tumor has metastasized. Such metastases can be microscopic and indolent, eluding detection with the most sensitive scanning and biochemical screening. Therefore, it is best to think of these tumors as either having detectable metastases (metastatic pheochromocytoma) or having no detectable metastases.

It is conceivable that all pheochromocytomas and paragangliomas metastasize single cells but that such cells will only grow if certain genes are downregulated and other genes upregulated. This concept is supported by genome-wide expression profiling of pheochromocytomas. These profiles have identified candidate genes that are differentially expressed in tumors with detectable metastases versus those with no detectable metastases. Gene expression arrays of pheochromocytomas with detectable metastases have demonstrated that five genes are differentially upregulated in these tumors.

Research in malignant pheochromocytoma has been hampered by the absence of a viable human cell line. However, a highly malignant mouse pheochromocytoma model has been developed in which a gene expression array has demonstrated the upregulation of 8 genes and the downregulation of 38 genes.

The risk for detectable metastases is higher under the following circumstances: extra-adrenal location (paraganglioma) or extensive local invasion. One surgical observation is that tumors that are stickier and more difficult to dissect from adjacent tissue are more likely to recur or metastasize. Tumors are also more likely to metastasize if they contain high levels of Ki-67, a protein expressed in proliferating cells that can be detected by the monoclonal antibody MIB-1 and quantified as a high MIB-1 score. Metastatic pheochromocytomas also have increased activity of telomerase. Tumors with high c-myc gene expression are more likely to be malignant. In one series, 50% of patients with malignant pheochromocytoma were found to have high serum levels of NSE, but in none of 13 patients in another series with benign pheochromocytomas.

Metastases are evident at the time of diagnosis in about 10% of patients with an adrenal pheochromocytoma. Another 5% to 10% are found to have metastatic disease or local recurrence within 20 years. In genetic syndromes, pheochromocytomas have been found to be metastatic or locally invasive at the time of diagnosis as follows: MEN 2A, 4%; VHL, 8%; and NF-1, 12%. Extra-adrenal paragangliomas commonly metastasize. In a Mayo Clinic series of paragangliomas, 15% had local invasion and 21% had detectable distant metastases at the time of initial surgery, with an overall 36% risk of local or distant metastasis.

Malignancy is determined only by the presence of metastases. CT or MRI scanning may not detect small metastases within their field and will certainly not visualize metastases outside their field. Therefore, following the resection of an apparently benign PHEO or PGL, long-term surveillance is required because metastases may not become clinically apparent for years or decades. Such surveillance includes regular lifetime clinical assessment and biochemical testing as indicated. Plasma-fractionated metanephrines is the most sensitive test to detect early recurrence or metastases. However, screening for metastases from nonsecretory paragangliomas should include serum CgA determinations. Plasma metanephrines and serum CgA usually fall into the normal range by 2 weeks following successful resection of a single benign pheochromocytoma. However, normal postoperative tests are not reliable indicators of benignancy, because small or nonsecretory metastases may still be present.

The differential diagnosis for apparent metastases includes second paragangliomas, multicentric paragangliomas, second pheochromocytomas, false-positive scanning, and intraperitoneal seeding of tumor (pheochromocytomatosis).

Sites of metastasis (see Table 11–17): Metastases from pheochromocytomas or paragangliomas typically involve bones (82%), liver (30%), lungs (36%), lymph nodes, the contralateral adrenal, and sometimes muscle. The bones most frequently involved include vertebrae, pelvis and ischium, clavicles, cranium, and proximal femurs and humeri. Tibia, radius, and ulna are occasionally involved. Patients with metastases and an SDHB mutation have a higher prevalence of metastases involving long bones compared to those without the mutation. PHEO/PGL metastases have a proclivity for the skull where they may form a dumbbell-type lesion, sometimes being palpable as a soft cyst-like bump; they also may grow inside the skull to impinge upon the brain. Prevertebral paragangliomas may destroy adjacent vertebrae, and spinal cord compression may occur. Most bone metastases affect the cortical bone; they may be indolent, but are often osteolytic and cause progressive bone destruction. Other bone metastases primarily involve trabecular bone and marrow; such metastases are usually visible on MRI but may be invisible on CT. Metastases to lymph nodes outside the abdomen are most frequent in the supraclavicular and inguinal regions. Metastases to muscle are usually indolent. These tumors have not been reported to metastasize to brain, although metastases to the cranium and skull base may impinge upon the brain, pituitary, and cranial nerves.

Metastases usually secrete norepinephrine and normetanephrine. Some metastases secrete predominantly dopamine. Metastases rarely secrete epinephrine or metanephrine, with the exception of some metastases from epinephrine-secreting adrenal pheochromocytomas. About 20% of primary paragangliomas and their metastases do not secrete catecholamines or metanephrines, but most continue to secrete CgA, which becomes a valuable tumor marker.

Assessing the growth rate of PHEO/PGL metastases: Treatment can be tailored to the tumor's rate of growth. Knowledge of the growth rate of a patient's metastases may be obtained through close biochemical surveillance and serial volumetric imaging with CT or MRI. Patients who are asymptomatic with a few indolent osseous metastases may elect to receive bisphosphonate therapy and delay life-threatening chemotherapy or radioisotope therapy, as long as they remain under close surveillance. Even patients with a symptomatic osteolytic metastasis may elect to receive targeted therapy rather than systemic treatment if their overall tumor burden is low.

Surveillance: A series of 110 Swedish patients with PHEO/PGL, treated surgically, found an unexpectedly high relative risk for developing non-PHEO/PGL malignancies (RR ≅2.0). Therefore, additional tumors should not be presumed to be metastases unless they have uptake on MIBG scanning or 18FDA-PET scanning. Suspicious lesions without such uptake should be considered for biopsy. Patients with hereditary forms of PHEO or PGL can present with bilateral disease or develop second primaries, distinct from metastatic disease.

Biochemical surveillance: Such screening is best done with plasma-fractionated metanephrines and catecholamines (with dopamine), along with serum CgA. While this is sensitive for secretory metastases, false-positive testing occurs commonly. Adrenal PHEOs usually secrete both norepinephrine and epinephrine; metastases from adrenal PHEOs may sometimes continue to produce epinephrine, but more commonly produce norepinephrine and its metabolite normetanephrine. Extra-adrenal PGLs ordinarily produce only norepinephrine and normetanephrine and sometimes only CgA; their metastases do likewise.

Scan surveillance: CT or MRI scanning is the most sensitive for recurrence; however, they will not detect metastases that are outside their field and obtaining full-body CT or MRI scanning is logistically difficult. Radionuclide scanning is advantageous in that the entire body may be included in the scan. However, no radionuclide scan is 100% sensitive. PHEO/PGL metastases have variable avidity for MIBG. Even when the primary tumor is avid for MIBG, some or all of the metastases may not be visible on MIBG scanning. Some metastases are deficient in norepinephrine transporter (NET) expression and are invisible on 123I-MIBG scanning, such that the scan's sensitivity for metastasis is only 57%. In a given individual, some metastases may be avid for MIBG, while others show virtually no uptake. When patients have a recurrence or progression of metastases after 131I-MIBG therapy, metastases with less MIBG-avid are usually the ones that emerge or progress in size. When such imaging is negative, metastases may be detected with MRI or CT scanning. Metabolically active metastases are usually visible with 18F-FDG-PET scanning, which has the additional advantage of being a whole-body scan with a sensitivity of about 76% for metastases. 18F-FDA-PET has a sensitivity of about 78% for metastases. Octreoscan will often detect metastases that are not visible with other scans.

Surgery

It is usually best to resect the primary tumor as well as large metastases. This is especially true of secretory tumors that are causing hypertension and other symptoms that can be a threat to life. Even lung metastases may be resected. However, the decision about whether to resect metastases is a difficult one and must be based upon very thorough staging of the patient's tumor. Of course, when resecting secretory metastases, preoperative preparation is mandatory and hypertension must be adequately controlled.

Chemotherapy

Due to the rarity of pheochromocytoma and paraganglioma, there have been no large-scale series comparing available chemotherapies. However, there have been small series of patients and case reports from which to derive recommendations.

In vitro studies have found that cultured pheochromocytoma cells are protected from cytotoxic insult by amitriptyline and fluoxetine, possibly through upregulation of superoxide dismutase. Therefore, patients being treated for metastatic pheochromocytoma or paraganglioma should probably not take tricyclic antidepressants or selective serotonin reuptake inhibitors, although there have been no in vivo studies of their effect on survival.

Cyclophosphamide, vincristine, dacarbazine (CVD): In one series, 8 of 14 patients responded to this regimen, with a median remission of 21 months. CVD was delivered over 2 days and the cycles repeated every 3 to 4 weeks, indefinitely. After controlling symptoms of catecholamine excess, cycles of CVD were administered as follows: cyclophosphamide 750 mg/m2, vincristine 1.4 mg/m2, and dacarbazine 600 mg/m2 on day 1, followed by dacarbazine 600 mg/m2 on day 2. Metastases progressed in 9 of the 14 patients, and there were 6 deaths with short-term follow-up. About one-third of patients appear to have a sustained remission or stable disease, as long as CVD is continued. When chemotherapy is stopped, the tumors usually recur. Many patients cannot tolerate such a long-term regimen, due to fatigue, cytopenias, neuropathy, and other adverse reactions. However, some patients tolerate it reasonably well and may experience a complete biochemical remission. Once in remission, CVD cycles are continued at gradually increasing intervals. If complete biochemical remission is achieved, chemotherapy may be stopped, while the patient is kept under close surveillance for progressive disease.

Sunitinib: Partial remissions in metastatic pheochromocytoma have been reported with sunitinib, a tyrosine kinase inhibitor. Sunitinib is administered orally, usually in a dose of 50 mg daily in cycles of 4 weeks on, then 2 weeks off. The dosage may be adjusted in 12.5-mg increments according to response and toxicity. Sunitinib is metabolized in the liver by CYP3A4, so dose adjustments should be made for patients taking the wide variety of drugs that are inhibitors or inducers of CYP3A4. Sunitinib can cause serious adverse reactions, including heart failure, cardiac arrhythmias, marrow suppression, pancreatitis, hypo- or hyperthyroidism, nephrotic syndrome, and rhabdomyolysis with acute renal failure. Patients treated with sunitinib also commonly experience nausea, vomiting, diarrhea, hypertension, skin discoloration, mucositis, asthenia, dyspnea, myalgias, and arthralgias. The use of sunitinib has been limited by its expense.

Bisphosphonates

No controlled clinical trials have assessed the efficacy of bisphosphonates against osteolytic bone metastases from paragangliomas and pheochromocytomas. However, bisphosphonates have demonstrated effectiveness in other osteolytic solid tumors to reduce skeletal-related adverse events. Zoledronic acid is usually administered every 1 to 2 months as an intravenous infusion to patients with osteolytic bone metastases. Patients unable to tolerate zoledronic acid may tolerate intravenous pamidronate.

Radiation Therapy

When administered to patients with symptomatic spinal or cranial metastases, radiation therapy can reduce pain and produce neurologic improvement. Although conventional radiation therapy is usually administered, Gamma Knife can be given to smaller symptomatic bone metastases. Conventional radiation therapy to large primary tumors or intra-abdominal metastases is not advisable, because it is usually ineffective and causes morbidity such as radiation enteritis and a proclivity to later surgical complications such as wound dehiscence, infections, and fistulas. However, small recurrent tumors can be treated with CyberKnife stereotactic radiosurgery. Radiation therapy to tumors reduces their uptake of 131I-MIBG. Surgical debulking of large abdominal or thoracic tumors (or other therapies) is usually preferable to radiation therapy.

Arterial Embolization and Radiofrequency Ablation

Before arterial embolization or radiofrequency ablation, patients with secretory pheochromocytomas or paragangliomas must be fully prepared such that their blood pressure is near normal as described earlier. Pretreatment includes alpha blockade and/or other measures such as beta blockade, calcium channel blockers, or metyrosine. Patients are monitored with arterial blood pressure transducers and given a central line before endotracheal general anesthesia. Anesthesia standby is necessary in case severe hypertension occurs, and it becomes necessary to administer intravenous antihypertensive drugs.

Arterial embolization has been used on rare occasions to reduce blood flow to paragangliomas and pheochromocytomas, either in preparation for surgery or for inoperable cases. These tumors are usually very vascular and preoperative embolization may reduce intraoperative hemorrhage. Also, embolizing the tumor's blood supply may slow its growth. However, there have been no controlled clinical trials as to its effectiveness. A major potential risk of embolization is that of pheochromocytoma crisis. However, embolization has been used successfully on secretory tumors where the patient has been fully prepared with alpha blockade and/or other measures. Localization arteriograms should use nonionic contrast.

Radiofrequency (RF) thermal ablation has been used successfully for patients with metastatic PHEO/PGL, particularly for liver and bone metastases. Most reported RF ablations of bone metastases have targeted rib or ischial/pelvic lesions. Before RF ablations, the RF electrode(s) is guided into the tumor with ultrasound and CT guidance. Single electrodes may be used for small lesions, while metastases over 2.5 cm diameter usually require triple parallel cluster needle electrodes.

131I-MIBG Therapy

(Figure 11–13)

131I-MIBG is a treatment option for patients with metastatic or unresectable pheochromocytoma or paraganglioma whose tumors are avid for the isotope. 131I-MIBG therapy was developed at the University of Michigan and first administered to patients with metastatic pheochromocytomas in 1983. Subsequently, many other patients have been treated with 131I-MIBG. Treatment protocols have employed repeated doses of 100 to 200 mCi (3.7-7.4 GBq) or larger single doses of 500 to 1000 mCi (18.5-37 GBq). Uptake occurs in many nonfunctioning pheochromocytomas and metastases, and such treatment can be effective for these tumors as long as scanning demonstrates that they are avid for MIBG. Following therapy with 131I-MIBG, once background radiation has dissipated, a posttreatment whole-body scan is obtained.

High-dose 131I-MIBG therapy (≥500 mCi) is available at several medical centers in the United States and Europe. Precautions must be taken before giving 131I-MIBG that exceeds 500 mCi or 12 mCi/kg body weight, since high doses of radioactive isotope can cause serious bone marrow suppression. Before 131I-MIBG therapy, patients are premedicated with potassium iodide to reduce the risk of thyroid damage that could be caused by any free 131I generated through metabolism of 131I-MIBG. Patients are pretreated with nonphenothiazine antiemetics; they remain hospitalized in lead-shielded rooms until the emitted gamma radiation declines to acceptable levels, which usually requires about 5 to 7 days.

Complete or partial remissions, defined by strict RECIST (Response Evaluation Criteria in Solid Tumors), occur in about 22% of patients treated with 131I-MIBG, while an additional 35% have minor responses and 8% have stable disease. However, 35% of patients experience progressive disease within a year after therapy. High-dose 131I-MIBG appears to improve 5-year survival. It predictably causes some degree of bone marrow suppression that commences about 2.5 weeks after therapy. Other adverse reactions include nausea, occasional sialadenitis, and transient hair, hypogonadism, infertility, and an increased lifetime risk of second malignancies, particularly myelodysplasia and leukemia. ARDS and bronchiolitis obliterans organizing pneumonia (BOOP) are rare complications of treatment with 131I-MIBG that have rarely occurred in patients treated with doses over 800 mCi. Repeated treatments may be required.

About 30% to 40% of patients with metastatic PHEO or PGL have insufficient uptake of MIBG for treatment to be effective. Also, there can be variable MIBG uptake into metastases in a given patient. So, theoretically, therapy with 131I-MIBG could be made more effective if the tumor's uptake of MIBG could be increased. Pretreatment with nifedipine increased MIBG retention in four of eight patients in one report. Some patients with good uptake of MIBG on diagnostic scanning have disappointingly poor uptake of large therapeutic doses of 131I-MIBG, possibly caused by competitive inhibition by large amounts of nonradioactive 127I-MIBG that are present in most formulations of 131I-MIBG.

Prognosis

The mortality rate for patients undergoing pheochromocytoma resection has dropped to under 3% due to improved medical preparation and surgical technique. Laparoscopic resections have reduced perioperative morbidity and shortened the length of hospitalization. However, even after complete resection of the pheochromocytoma, hypertension persists or recurs in 25% of patients. Recurrent hypertension is an indication for reevaluation for pheochromocytoma.

Following surgical resection of a benign pheochromocytoma, patients have a 5-year survival rate of 96%. Risk factors for death from pheochromocytoma include tumor size over 5 cm, metastatic disease, and local tumor invasion. However, the long-term mortality rate is much higher than expected. In a Swedish long-term outcome study of 121 patients with pheochromocytoma, there was no perioperative mortality, but 50% of patients remained hypertensive postoperatively. Of the 121 patients, 42 died during an observation period averaging 15 years, versus an expected 24 deaths in an age-matched control population. Thus, their relative risk of mortality was increased 78% (1.78). Of the 42 patients who died, 20 deaths were due to cardiovascular disease, 6 from associated neuroectodermal tumors, 5 from other malignancies, 7 from unrelated causes, and 4 from malignant pheochromocytoma.

Patients with pheochromocytoma or paraganglioma metastases have an average 5-year survival of about 50% from the time that metastases are detected. However, for patients in whom close surveillance and scanning find presymptomatic metastases, the average 5-year survival is probably longer, simply because the metastases are diagnosed at an earlier stage. Also, metastases are variably aggressive, between patients and within a given patient. Some metastases are quite indolent and may present clinically one or two decades after resection of the primary tumor. However, other metastases are exceptionally aggressive. Asymptomatic patients with only a few bone metastases tend to have the best prognosis, while those with a heavy burden of liver and lung metastases tend to have the most malignant disease.

Pheochromocytoma: Postoperative Long-Term Surveillance

All patients with pheochromocytomas require long-term postoperative surveillance. They require lifetime surveillance and aggressive treatment of all cardiovascular risk factors, due to their increased long-term risk of death from cardiovascular causes. Additionally, patients should be tested for familial genetic syndromes and appropriately screened for associated malignancies (see “Genetic Conditions Associated with Pheochromocytomas and Paragangliomas,” Tables 11–8 through 11–11). Persistent symptoms or hypertension can signify recurrence at the surgical site, seeding of the peritoneum, a contralateral pheochromocytoma, a paraganglioma, or possibly metastatic disease. About 10% of pheochromocytomas have metastasized at the time of diagnosis or soon postoperatively. However, occult metastatic disease is detected up to 20 years later in another 5%. Other patients develop multiple recurrent intra-abdominal tumors (pheochromocytomatosis) probably caused by tumor seeding that may occur spontaneously from the original tumor or during surgery.

Patients with secretory tumors are usually followed with plasma-fractionated free metanephrine determinations. Plasma-fractionated catecholamines and dopamine may also be obtained if they were predominantly secreted by the primary tumor. The first determination of postoperative plasma-fractionated free metanephrines is obtained at least 2 weeks after surgery, because catecholamine excretion often remains high for up to 10 days after successful surgery. Testing is obtained quarterly during the first year following surgery, then annually or semiannually for at least 5 years. Serum CgA is a useful tumor marker for patients with pheochromocytomas whose primary tumor secreted CgA and whose renal function is normal; elevated and rising levels of CgA usually indicate tumor recurrence or metastases. (See Chromogranin A, earlier.) Rarely, nonfunctioning tumors may later develop functioning metastases. Lifetime medical follow-up is required. Patients should continue to have annual physical examinations for life. Long-term biochemical follow-up is tailored to the individual patient.

For hypertensive patients, weekly home blood pressure monitoring is recommended for the first year postoperatively and monthly afterward. A rising blood pressure or recurrence of symptoms should trigger a full work-up for recurrent or metastatic pheochromocytoma.

A postoperative 123I-MIBG scan or PET scan is recommended for all patients—but especially for those in whom there is any doubt about complete resection of the pheochromocytoma and for any patients with paraganglioma or multiple tumors. The postoperative scan is usually obtained several months after surgery. PET scanning is particularly useful for patients with metastatic PHEO/PGL or nonsecreting paragangliomas.

Adrenal Medulla and Adrenergic Physiology

Autonomic Insufficiency

Pheochromocytoma and Paranglioma Reviews

Pheochromocytoma Pathophysiology

Genetic Aspects of Pheochromocytoma and Paraganglioma

Diagnostic Tests and Differential Diagnosis for Pheochromocytoma

Localizing Scans for Pheochromocytoma and Paraganglioma

Incidental Adrenal Tumors

Medical Therapy for Pheochromocytoma

Pheochromocytoma in Pregnancy

Surgery for Pheochromocytoma and Paraganglioma

Radiation Therapy for Unresectable or Metastatic Paragangliomas and Pheochromocytomas

Radiation, Embolization and Radiofrequency Ablation of Paragangliomas, Pheochromocytomas, and Metastases

Metastatic Pheochromocytoma and Paraganglioma