Paul A. Fitzgerald MD
Alan Goldfien MD
The adrenal medulla is a specialized part of the sympathetic nervous system that secretes catecholamines. The sympathetic nervous system typically secretes norepinephrine as a local neurotransmitter directly in target organs. In comparison, the adrenal medulla is important for its secretion of epinephrine and other substances into the general circulation for widespread distribution and effect. Although the adrenal medulla is not critically necessary 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 paragangliomas arise from extra-adrenal sympathetic ganglia. These tumors can secrete excessive amounts of norepinephrine and epinephrine, causing a dangerous exaggeration of the stress response.
The adrenal medulla was initially distinguished from the adrenal cortex in the early 19th century. Pheochromocytomas were first described by Fränkel in 1886 after the sudden death of an 18-year-old woman who had been experiencing episodes of palpitations, pounding heart, headaches, retinitis, pallor, and vomiting. Autopsy disclosed bilateral adrenal tumors, ventricular hypertrophy, and nephrosclerosis. In 1896, Manasse found that chromium salts turned such tumors dark brown, a reaction typical of adrenal medullary tissue. They were later termed “chromaffin” tumors.
In 1901, the substrate of the chromaffin reaction was chemically identified as 3,4-dihydroxyphenyl-2-methylaminoethanol by two independent researchers: J. Takamine named the substance “adrenaline” in the Journal of Physiology in London, while T.B. Aldrich called it “epinephrine” in the American Journal of Physiology. To this day, the substance is generally termed “adrenaline”in the United Kingdom and “epinephrine” in the United States. Norepinephrine was synthesized in 1904.
Alezais and Peyronin coined the term “paraganglioma” in 1908 to denote chromaffin tumors arising from the paraganglia. In 1912, Pick coined the word “pheochromocytoma” from Greek phaios “dusky,” chroma “color,” and kytos “cell.” The term refers to the color change that occurs in such tumor tissue when exposed to certain fixatives: Dichromate stain (eg, Zenker's, Helly's, or Orth's stain) produces a brownish-yellow coloration of cells with neurosecretory granules. Cells that contain epinephrine turn dark brown,
whereas cells that contain norepinephrine turn pale yellow. Dilute Giemsa-Schmorl stain colors pheochromocytoma tissue green.
The first successful surgical resections of pheochromocytomas were performed in 1926 by C.H. Mayo at the Mayo Clinic and by Roux in Switzerland. In 1929, Rabin discovered that pheochromocytomas contain a pressor substance that could explain the clinical manifestations. However, it was not until 1939 that a patient with a pheochromocytoma was documented to have high blood levels of epinephrine. In 1946, von Euler found that the heart contains norepinephrine and that norepinephrine is the neurotransmitter for the sympathetic nervous system. In 1948, Alquist proposed the existence of two groups of adrenergic receptors that he designated α and β based on the relative potencies of a series of adrenergic agonists. In 1950, von Euler and Engel reported that urinary epinephrine and norepinephrine excretion was higher in patients with pheochromocytomas. Urinary collections for vanillylmandelic acid (VMA) were used to diagnose pheochromocytoma after Armstrong determined that VMA was a catecholamine metabolite. LaBrosse reported urinary normetanephrine excretion in 1958. Von Euler was awarded the Nobel Prize for Physiology in 1970.
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 primitive 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 by electron microscopy at 12 weeks. Pheochromoblasts and pheochromocytes also collect on both sides of the aorta to form the paraganglia. The principal collection of these cells is found at the level of the inferior mesenteric artery. They fuse anteriorly to form the organ of Zuckerkandl, which is quite prominent in fetal life. This organ is thought to be a major source of catecholamines during the first year of life, after which it begins to atrophy. The adrenal medullas are very small and amorphous at birth but develop into recognizable adult form by the sixth month of postnatal life. Pheochromocytes (chromaffin cells) also are found scattered throughout the abdominal sympathetic plexuses as well as in other parts of the sympathetic nervous system.
Figure 11-1. The embryonic development of adrenergic cells and tumors that develop from them (in parentheses). Sympathogonia are primitive cells derived from the neural crest. Neuroblasts are also called sympathoblasts; ganglion cells are the same as sympathocytes; and pheochromocytes are mature chromaffin cells.
The anatomic relationships between the adrenal medulla and the adrenal cortex differ in different species. These organs are completely separate structures in the shark. They remain separate but in close contact in amphibians, and there is some intermingling in birds. In mammals, the medulla is surrounded by the adrenal cortex. 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. It constitutes approximately one-tenth of the weight of the gland, although the proportions vary from individual to individual. There is no clear demarcation between cortex and medulla. The central vein is usually surrounded by a cuff of adrenal cortical cells, and there may be islands of cortex elsewhere in the medulla.
The chromaffin cells, or pheochromocytes, of the adrenal medulla are large ovoid columnar cells arranged in clumps or cords around blood vessels. These cells
have large nuclei and a well-developed Golgi apparatus. They contain large numbers of vesicles or granules containing catecholamines. Vesicles containing norepinephrine are darker than those containing epinephrine.
The pheochromocytes may be arranged in nests, alveoli, or cords and are surrounded by a rich network of capillaries and sinusoids. The adrenal medulla also contains some sympathetic ganglion cells, singly or in groups. Ganglion cells are also found in association with the viscera, the carotid body, the glomus jugulare, and the cervical and thoracic ganglia.
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 30–50 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.
The human adrenal gland derives blood from the superior, middle, and inferior adrenal branches of the inferior phrenic artery, directly from the aorta and from the renal arteries. Upon 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. It would appear, then, that most of the blood supply to the medullary cells is via a portal vascular system arising from the capillaries in the cortex. There is also a capillary network of lymphatics that drain into a plexus around the central vein.
In mammals, the enzyme that catalyzes the conversion of norepinephrine to epinephrine (phenylethanolamine-N-methyltransferase; PNMT) is induced by cortisol. The chromaffin cells containing epinephrine therefore receive most of their blood supply from the capillaries draining the cortical cells, whereas cells containing predominantly norepinephrine are supplied by the arteries that directly supply the medulla. (SeeBiosynthesis, below.)
On the right side, the central vein is short and drains directly into the vena cava, although some branches go to the surface of the gland and reach the azygos system. On the left, the vein is somewhat longer and drains into the renal vein.
HORMONES OF THE ADRENAL MEDULLA
Biosynthesis & Metabolism (Figures 11-2 and 11-3)
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 (Figure 11-2).
Figure. No caption available.
Catecholamines are widely distributed in plants and animals. In mammals, epinephrine is synthesized mainly in the adrenal medulla, whereas norepinephrine is found not only in the adrenal medulla but also in the central nervous system and in the peripheral sympathetic nerves. Dopamine, the precursor of norepinephrine, is found in the adrenal medulla and in noradrenergic neurons. It is present in high concentrations in the brain, in specialized interneurons in the sympathetic ganglia, and in the carotid body, where it serves as a neurotransmitter. Dopamine is also found in specialized mast cells and in enterochromaffin cells.
Chromogranin A (CgA) is a peptide that is stored and released with catecholamines by exocytosis; catestatin is a fragment of the 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. However, interestingly, lower catestatin levels have been noted in the offspring of hypertensive individuals. In white individuals, those with lower catestatin levels tend to have greater
adrenergic pressor responses. Thus, relative deficiencies in catestatin may increase the risk for later development of essential hypertension.
Figure 11-2. Biosynthesis of catecholamines. (PNMT, phenylethanolamine-N-methyltransferase.)
The proportions of epinephrine and norepinephrine found in the adrenal medulla vary with the species (Table 11-1). In humans, the adrenal medulla contains 15–20% norepinephrine.
- 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 1–1.5 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 is effective and is sometimes used in the therapy of malignant 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 upon 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 stored in the vesicle. 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, most circulating norepinephrine originates from diffusion out of nonadrenal sympathetic nerve cells.
- CONVERSION OF NOREPINEPHRINE TO EPINEPHRINE
Norepinephrine can diffuse into the cytoplasm from storage granules. In certain cells (particularly the adrenal medulla), norepinephrine is converted to epinephrine in the cytoplasm, catalyzed by 4-phenylethanolamine-N-methyltransferase (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 while only 20% is norepinephrine. Serum epinephrine levels fall precipitously after resection of both normal adrenals, while norepinephrine concentrations do not decline.
Figure 11-3. Metabolism of catecholamines by catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO).
Table 11-1. Approximate percentages of total adrenal medullary catecholamines present as norepinephrine in various species.
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; in vivo exposure of bronchial epithelial cell lines to dexamethasone increases the expression of PNMT. Thus, glucocorticoids could potentially increase local concentrations of epinephrine in the lung; this might be one potential mechanism for the effectiveness of systemic and inhaled glucocorticoids in asthma. PNMT activity is also found in red blood cells, where its activity is increased by hyperthyroidism and decreased by hypothyroidism. Renal PNMT activity is such that the kidney may synthesize up to one-half of the epinephrine found in the urine in normal individuals.
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. In the adrenal medulla, it is possible to deplete stores with prolonged hypoglycemia. Biosynthesis appears to be increased during nerve stimulation by activation of tyrosine hydroxylase. Prolonged stimulation leads to the induction of increased amounts of this enzyme.
Catecholamines are found in the adrenal medulla and various sympathetically innervated organs, and their concentration reflects the density of sympathetic neurons. The adrenal medulla contains about 0.5 mg/g; the spleen, vas deferens, brain, spinal cord, and heart contain 1–5 ľg/g; liver, gut, and skeletal muscle contain 0.1–0.5 ľg/g. Catecholamines are stored in electron-dense granules approximately 1 ľm in diameter that contain catecholamines and ATP in a 4:1 molar ratio, several neuropeptides, calcium, magnesium, and water-soluble proteins called chromogranins (see above). The interior surface of the membrane contains dopamine β-hydroxylase 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 the chromogranins are physiologically active and may modulate catecholamine release.
Secretion (Table 11-2)
Adrenal medullary catecholamine secretion is increased by 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, anoxia and asphyxia produce a greater increase in adrenal medullary release of norepinephrine than is observed with other stimuli.
Secretion of the adrenal medullary hormones is mediated by the release of acetylcholine from the terminals of preganglionic fibers. The resulting depolarization of the axonal membrane triggers an influx of calcium ion. The contents of the storage vesicles, including the chromogranins and soluble dopamine β-hydroxylase, are released by exocytosis by the calcium ion increase. Membrane-bound dopamine β-hydroxylase is not released. Tyramine, however, releases norepinephrine primarily from the free store in the cytosol. Cocaine and monoamine oxidase inhibitors inhibit the effect of tyramine but do not affect the release of catecholamines by nervous stimulation. The rate of release in response to nerve stimulation is increased or decreased by a wide variety of neurotransmitters acting at specific receptors on the presynaptic neuron. Norepinephrine has an important role in modulating its own release by activating the α2 receptors on the presynaptic membrane. Alpha2 receptor antagonists inhibit this reaction. Conversely, presynaptic beta receptors enhance norepinephrine release, whereas beta receptor blockers decrease it. The accumulation of excess catecholamines that are not in the storage granules is prevented by the presence of intraneuronal monoamine oxidase.
When released into the circulation, catecholamines are bound to albumin or a closely associated protein with low affinity and high capacity.
Table 11-2. Range of plasma catecholamine levels observed in healthy subjects and patients.
Metabolism & Inactivation of Catecholamines (Figures 11-3 and 11-4)
Catecholamines are quickly metabolized into inactive compounds, including metanephrines, VMA, and conjugated catecholamines.
Excess intracellular norepinephrine is inactivated primarily by deamination, catalyzed mainly by monoamine oxidase (MAO), at the outer mitochondrial membrane. (MAO regulates the catecholamine content of neurons; levels of MAO are increased by progesterone and decreased by estrogen.) The resultant aldehyde is then oxidized to 3,4-dihydroxymandelic acid (DHMA) or dihydroxyphenylglycol (DHPG); the latter are catalyzed by the enzyme catechol-O-methyltransferase (COMT) to VMA, which is then excreted. In pheochromocytomas, membrane-bound COMT metabolizes epinephrine into metanephrine; it converts norepinephrine into normetanephrine. These metanephrine metabolites are then secreted directly into the circulation. Thus, in patients with pheochromocytomas, about 93% of circulating normetanephrine comes from direct secretion from the tumor rather than from peripheral metabolism.
Catecholamines that are released at the synapse bind to their receptors with relatively low affinity and dissociate rapidly (Figure 11-4). About 15% of norepinephrine escapes from synapses into the systemic circulation. About 85% of synaptic catecholamines are reabsorbed by the nerves from which they were released or by the target cells, after which they may be stored for re-release or metabolized and released as described above. The catecholamine uptake mechanism is saturable, energy-requiring, stereoselective, and sodium-dependent. Synaptic catecholamine uptake is blocked by tricyclic antidepressants, phenothiazines, amphetamine derivatives, and cocaine.
Peripheral circulating norepinephrine is metabolized largely to normetanephrine by COMT, with the methyl donor being S-adenosylmethionine (SAM). COMT is an enzyme found in most tissues, especially blood cells, liver, kidney, and vascular smooth muscle. Epinephrine is similarly catabolized to metanephrine, some of which is then converted to VMA (Figure 11-3). Catecholamines may also be inactivated by conjugation of their phenolic hydroxyl group with sulfate or glucuronide; this reaction occurs mainly in the liver, gut, and red blood cells.
Catecholamines and metabolites 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 < 5% free catecholamines.
Adrenergic receptors were first classified by the relative potencies of a series of adrenergic agonists and antagonists. Each of the subtypes is now known to be coded for by one or more separate genes (Table 11-3). The physiologic effects mediated by them are summarized inTable 11-4.
The 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 (see Figure 3-2). 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. The G proteins consist of α, β, and γ subunits. There are many G proteins that have different α subunits while the β and γ subunits are similar. When 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
The α1 subtypes are postsynaptic receptors that typically mediate vascular and other smooth muscle contraction. When agonist binds to this 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 trisphosphate (IP3) and diacylglycerol. IP3 releases calcium ion from intracellular stores to stimulate physiologic responses. Diacylglycerol activates 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 (Figure 3-4). Epinephrine and norepinephrine are potent agonists for this receptor, while isoproterenol is weakly active.
Alpha2 receptors were first identified at the presynaptic sympathetic nerve ending and, when activated, served to inhibit the release of norepinephrine. However, these receptors have been found in platelets and postsynaptically in the nervous system, adipose tissue, and smooth muscle.
Agonist binding to the α2 receptor releases Gi alpha, which inhibits the enzyme adenylyl cyclase and reduces the formation of cAMP. Prazosin is a selective antagonist at the α1 receptor and yohimbine is selective for the α2, whereas phentolamine and phenoxybenzamine act at both (Table 11-3).
Figure 11-4. Schematic diagram of the neuroeffector junction of the peripheral sympathetic nervous system. The nerves terminate in complex networks with enlargements that form synaptic junctions with effector cells. The neurotransmitter at these junctions is norepinephrine, which is synthesized from tyrosine. Tyrosine uptake ① is linked to sodium uptake and transport into the varicosity where the secretory vesicles form. Tyrosine is hydroxylated by tyrosine hydroxylase to dopa, which is then decarboxylated by dopa decarboxylate to dopamine in the cytoplasm. Dopamine (DA) is transported into the vesicle by a carrier mechanism ② that can be blocked by reserpine. The same carrier transports norepinephrine (NE) and several other amines into these granules. Dopamine is converted to norepinephrine through the catalytic action of dopamine β-hydroxylase (DβH). ATP is also present in high concentration in the vesicle. Release of transmitter occurs when an action potential is conducted to the varicosity by the action of voltage-sensitive sodium channels. Depolarization of the synaptic membrane opens voltage-sensitive calcium channels and results in an increase in intracellular calcium. The elevated calcium facilitates exocytotic fusion of vesicles with the surface membrane and expulsion of norepinephrine, ATP, and some of the dopamine β-hydroxylase. Release is blocked by drugs such as guanethidine and bretylium. Norepinephrine reaching either pre- or postsynaptic receptors modifies the function of the corresponding cells. Norepinephrine also diffuses out of the cleft, or it may be transported into the cytoplasm of the varicosity (uptake 1, blocked by cocaine, tricyclic antidepressants) ③ or into the postjunctional cell (uptake 2) ④ (Reproduced, with permission, from Katzung BG [editor]: Basic & Clinical Pharmacology, 5th ed. McGraw-Hill, 1992.) (Note: In pheochromocytomas, membrane-bound COMT within tumor cells metabolizes epinephrine and norepinephrine directly into metanephrine and normetanephrine, respectively, which are then released.)
Table 11-3. Adrenoceptor types and subtypes.1
- BETA-ADRENERGIC RECEPTORS
Agonist binding to the beta-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 3-4). There are three major beta-receptor subtypes. The β1 receptor, which mediates the direct cardiac effects, is more responsive to isoproterenol than to epinephrine or norepinephrine, whose potencies are similar. The β2 receptor mediates vascular, bronchial, and uterine smooth muscle relaxation, probably by phosphorylating myosin light chain kinase. Isoproterenol is also the most potent agonist at this receptor, but epinephrine is much more potent than norepinephrine. Beta2 receptor polymorphisms are associated with differences in sensitivity to albuterol in asthmatics and with obesity in women. The β3 receptors regulate energy expenditure and lipolysis. Homozygous mutations in the β3 gene in Pima Indians are associated with earlier onset of type 2 diabetes. Resting autonomic nervous system activity is reduced in homozygous and heterozygous patients with Trp(64)-Arg polymorphism of the β3 receptor. In the heart, β3 stimulation causes decreased ventricular contraction by increasing nitric oxide.
Table 11-4. Adrenergic responses of selected tissues.
- DOPAMINE RECEPTORS
Dopaminergic receptors are found in the central nervous system, presynaptic adrenergic nerve terminals, pituitary, heart, renal and mesenteric vascular beds, and other sites. Five subtypes of the dopaminergic receptor, D1 to D5, have been identified. The binding affinity of the D1 receptor is greater for dopamine than for haloperidol; the reverse is true for the D2 receptor. The effects of the D1 receptor are mediated by stimulation of the adenylyl cyclase system and are found postsynaptically in the brain. Those in the pituitary are D2 receptors that inhibit the formation of cAMP, open potassium channels, and decrease calcium influx.
Regulation of Activity
The major physiologic control of sympathoadrenal activity is exerted by alterations in the rate of secretion of the catecholamines. However, the receptors and postreceptor events serve as sites of fine regulation.
As noted above, presynaptically, norepinephrine released during nerve stimulation binds to alpha receptors and reduces the amount of norepinephrine released.
The number of receptors on the effector cell surface can be reduced by binding of agonist to receptor (antagonists do not have the same effect). This reduction is called “down-regulation.” Thyroid hormone, however, has been shown to increase the number of beta receptors in the myocardium. Estrogen, which increases the number of alpha receptors in the myometrium, increases the affinity of some vascular alpha receptors for norepinephrine.
The mechanisms involved in some of these changes are known. For example phosphorylation of the beta-adrenergic receptor by beta-adrenergic receptor kinase results in their sequestration into membrane vesicles, internalization, and degradation. The phosphorylated receptor also has a greater affinity for β-arrestin, another regulatory protein, which prevents its interaction with Gsα.
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. In contrast, the effects of the adrenal medulla are mediated via the circulating catecholamines and, therefore, are much more generalized in nature. Furthermore, adrenal medullary secretion increases significantly only in the presence of stress or marked deviation from homeostatic or resting conditions.
Catecholamine Actions (Figure 11-4)
Dopamine is an important central neurotransmitter and a precursor to norepinephrine. Circulating dopamine is not normally a significant catecholamine; the presence of dopamine in the urine is mainly due to high renal concentrations of dopa decarboxylase. Higher serum concentrations of dopamine stimulate vascular D1 receptors, causing vasodilation and increased renal blood flow. Extremely high serum levels of dopamine are required to activate vascular alpha receptors enough to cause vasoconstriction.
Norepinephrine is synthesized in the adrenal medulla, sympathetic paraganglia, brain, and spinal cord nerve cells. However, most norepinephrine is 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.
Figure 11-5. Activation of α1 responses. Stimulation of α1 receptors by catecholamines leads to the activation of a Gq coupling protein. The alpha subunit of this G protein activates the effector, phospholipase C, which leads to the release of IP3 (inositol 1,4,5-trisphosphate) and DAG (diacylglycerol) from phosphatidylinositol 4,5-bisphosphate (PtdIns 4,5-P2). IP3YY stimulates the release of sequestered stores of calcium, leading to an increased concentration of cytoplasmic Ca2+. Ca2+ may then activate Ca2+-dependent protein kinases, which in turn phosphorylate their substrates. DAG activates protein kinase C. See text for additional effects of α1receptor activation. (Reproduced, with permission, from Katzung BJ [editor]: Basic & Clinical Pharmacology, 8th ed. McGraw-Hill, 2001.)
Norepinephrine stimulates α1-adrenergic receptors, which increases 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. α1-Adrenergic activation stimulates sweating from nonthermoregulatory apocrine “stress” sweat glands, which are located variably on the palms, axillae, and forehead. Norepinephrine's activation of β-adrenergic receptors causes an influx of calcium into the target cell. Norepinephrine has great affinity for β1-adrenergic receptors (increases cardiac contraction and rate); stimulation of the heart rate is opposed by simultaneous vagal stimulation. Norepinephrine has less affinity for β2-adrenergic receptors (vasodilation, hepatic glycogenolysis). With higher 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 also 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.” These manifestations are distinct from those of noncatecholamine amphetamines, which
enter the central nervous system more readily and have other stimulatory effects.
- CARDIOVASCULAR EFFECTS
Catecholamines increase the rate and force of contraction and increase the irritability of the myocardium, primarily by activating β1receptors. The contractile effects of the catecholamines on vascular smooth muscle are regulated by α1, α2, and β2 receptors. Contraction is mediated by the α1 receptor, and although beta receptors are present and cause dilatation, other mechanisms of vascular dilatation are probably more important in vasoregulatory control. The release or injection of catecholamines can therefore be expected to increase heart rate and cardiac output and cause peripheral vasoconstriction—all leading to an increase in blood pressure. These events are modulated by reflex mechanisms, so that, as the blood pressure increases, reflex stimulation may slow the heart rate and tend to reduce cardiac output. Although norepinephrine in the usual doses will have 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 increasing the heart rate and cardiac output. In an individual with a reduction in vascular tone, the mean blood pressure would be expected to increase. In addition to the reflex mechanisms, vascular output 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 ordinary 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. The infusion of catecholamines leads to a rapid reduction in plasma volume, presumably to accommodate the reduced volume of the arterial and venous beds (Figure 11-6).
- EFFECTS ON EXTRAVASCULAR SMOOTH MUSCLE
The catecholamines also regulate the activity of smooth muscle in tissues other than blood vessels. These effects include relaxation and contraction of uterine myometrium, relaxation of intestinal and bladder smooth muscle, contraction of the smooth muscle in the bladder and intestinal sphincters, and relaxation of tracheal smooth muscle and pupillary dilatation.
- METABOLIC EFFECTS
The catecholamines increase oxygen consumption and heat production. Although the effects appear to be mediated by the beta receptor, the mechanism is unknown. The catecholamines also regulate glucose and fat mobilization from storage depots. Glycogenolysis in heart muscle and in 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 for utilization at other sites. In humans, these effects are mediated by the beta receptor.
Figure 11-6. Changes in plasma volume produced by infusion of norepinephrine for 20 minutes in a dose sufficient to increase mean arterial pressure from 96 ą 10 mm Hg to 150 ą 16 mm Hg. (Data from Finnerty FA Jr, Buchholz JH, Guillaudeu RL: Blood volumes and plasma protein during arterenol-induced hypertension. J Clin Invest 1958;37:425.)
The plasma levels of catecholamines required to produce some cardiovascular and metabolic effects in humans are shown in Table 11-5.
The catecholamines have effects on water, sodium, potassium, calcium, and phosphate excretion in the kidney. However, the mechanisms and the significance of these changes are not clear.
The Regulatory Role of Catecholamines in Hormone Secretion
The sympathetic nervous system plays an important role in the regulation and integration of hormone secretion at two levels. Centrally, norepinephrine and dopamine
play important roles in the regulation of secretion of the anterior pituitary hormones. Dopamine, for example, has been identified as the prolactin-inhibiting hormone, and the hypothalamic releasing hormones appear to be under sympathetic nervous system control. Peripherally, the secretion of renin by the juxtaglomerular cells of the kidney is regulated by the sympathetic nervous system via the renal nerves and circulating catecholamines. The catecholamines release renin via a beta receptor mechanism. The B cell of the pancreatic islets is stimulated by activation of the beta receptors in the presence of alpha-adrenergic blockade. However, the dominant effect of norepinephrine or epinephrine is inhibition of insulin secretion, which is mediated by the alpha receptor. Similar effects have been observed in the secretion of glucagon by pancreatic A cells. The catecholamines have also been found to increase the release of thyroxine, calcitonin, parathyroid hormone, and gastrin by a beta receptor-mediated mechanism.
Table 11-5. Approximate circulating plasma levels of epinephrine and norepinephrine required to produce hemodynamic and metabolic changes during infusions of epinephrine and norepinephrine.1
In addition to the catecholamines, the chromaffin cells of the adrenal medulla and peripheral sympathetic neurons synthesize and secrete opiate-like peptides, including met- and leu-enkephalin (see Chapter 5). They are stored in the large, dense-cored vesicles with the catecholamines in the adrenal medulla and at sympathetic nerve endings. These peptides are also found in the terminals of the splanchnic fibers that innervate the adrenal medulla. The observation that naloxone increases plasma catecholamine levels suggests that these peptides may inhibit sympathetic activity.
Adrenomedullin, a peptide originally isolated from pheochromocytoma tissue, is produced in the adrenal medulla. It consists of 52 amino acids, has slight homology with calcitonin gene-related peptide, and exerts its effects by elevation of cAMP levels. It exhibits potent depressor and vasorelaxant activity. It has also been found in the heart, lung, kidney, and brain as well as vascular endothelium. Adrenomedullin is a vasodilatory and natriuretic peptide and is secreted by the heart in heart failure. Adrenomedullin circulates in blood, and plasma levels in patients with hypertension have been reported to be higher than those of normotensive controls. It is thought to play a role in blood pressure regulation. The amino terminal 20-amino-acid peptide of proadrenomedullin from which adrenomedullin is derived is also found in the same tissues. This peptide also exhibits hypotensive effects, but it appears to do so by inhibiting neural transmission at sympathetic nerve endings rather than directly relaxing vascular smooth muscle like adrenomedullin.
Vasopressin is produced by the adrenal medulla. Its receptors (V1a and V1b) are also present and are thought to regulate catecholamine secretion. Extracts of normal adrenals have also been found to contain corticotropin-releasing factor, growth hormone-releasing hormone, somatostatin, and peptide histidine methionine. Although these and other active peptides are secreted by tumors of the adrenal medulla and contribute to the symptomatology, little is known of their function in the normal gland.
DISORDERS OF ADRENAL MEDULLARY FUNCTION
ADRENAL MEDULLARY HYPOFUNCTION
Hypofunction of the adrenal medulla alone probably occurs only in individuals receiving adrenocortical steroid replacement therapy following adrenalectomy. Such individuals with otherwise intact sympathetic nervous systems suffer no clinically significant disability. Patients with autonomic insufficiency, which includes
deficiency of adrenal medullary epinephrine secretion, can be demonstrated to have minor defects in recovery from insulin-induced hypoglycemia (Figure 11-7). It should be noted, however, that 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 severe bouts of hypoglycemia. This is the result of a decrease in the warning symptoms as well as an impaired response. (See Chapter 18.) Patients with generalized autonomic insufficiency usually have orthostatic hypotension. The causes of disorders associated with autonomic insufficiency are listed in Table 11-6.
Table 11-6. Disorders associated with autonomic insufficiency.
Figure 11-7. Plasma glucose, epinephrine, and norepinephrine levels after insulin administration in 14 normal subjects (•–•) and seven patients with idiopathic orthostatic hypotension (•–•) with low or absent epinephrine responses. Results are expressed as mean ą SEM. (Reproduced, with permission, from Polinsky RJ et al: The adrenal medullary response to hypoglycemia in patients with orthostatic hypotension. J Clin Endocrinol Metab 1980;51:1404.)
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.
The treatment of symptomatic orthostatic hypotension is dependent upon maintenance of an adequate blood volume. If physical measures such as raising the foot of the bed at night and using support garments do not alleviate the condition, pharmacologic measures may be used. Although agents producing constriction of the vascular bed, including ephedrine, phenylephrine, metaraminol, monoamine oxidase inhibitors, levodopa, propranolol, and indomethacin, have been used, volume expansion with fludrocortisone is the most effective treatment. Octreotide alone or in combination with the adrenergic agonist midodrine have also been shown to be effective in many patients.
ADRENAL MEDULLARY HYPERFUNCTION
The adrenal medulla is not known to play a significant role in essential hypertension. However, the role of the sympathetic nervous system in the regulation of blood flow and blood pressure has led to extensive investigations of its role in various types of hypertension. Some of the abnormalities observed, such as a resetting of baroreceptor activity, are thought to be secondary to the change in blood pressure. Others, such as the increased cardiac output found in early essential hypertension, have been thought by some investigators to play a primary role.
Catecholamines can increase blood pressure by increasing cardiac output, by increasing peripheral resistance through their vasoconstrictive action on the arteriole, and by increasing renin release from the kidney, leading to increased circulating levels of angiotensin II. Although many studies show an increase in circulating free catecholamine levels, evidence of increased sympathetic activity has not been a uniform finding in patients with essential hypertension.
Pheochromocytomas are rare tumors. The National Cancer Registry in Sweden has reported that pheochromocytomas are discovered in about two 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 pheochromocytomas at autopsy occurred in patients who were known to have had hypertension; about 91% had the typical but nonspecific symptoms associated with secretory pheochromocytomas. In one autopsy study, a large number of patients with pheochromocytoma had nonclassic symptoms such as abdominal pain, vomiting, dyspnea, heart failure, hypotension, or sudden death (Table 11-7). Considering these autopsy data, it is clear that the great majority of pheochromocytomas are not diagnosed during life. This is due to the protean manifestations of pheochromocytoma. Clearly, physicians must become more vigilant for pheochromocytoma and employ appropriate screening tests for all patients in whom pheochromocytoma enters into the differential diagnosis. Pheochromocytomas occur in both sexes and at any age but are most common in the fourth and fifth decades.
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. The incidence of pheochromocytoma is estimated to be < 0.1% of the entire hypertensive population, but it is higher in certain subgroups whose hypertension is labile or severe. Screening for pheochromocytoma 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 (Tables 11-8 and 11-9).
Pathology of Pheochromocytomas & Related Tumors
Pheochromocytomas are usually located in the adrenals (90% in adults, 70% in children), occurring more frequently on the right than on the left. In one series, right-sided pheochromocytomas were 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. They may present at any age but appear more commonly in the fourth and fifth decades.
Table 11-7. Causes of death in patients with unsuspected pheochromocytomas.
Table 11-8. Patients to be screened for pheochromocytoma.
Most sporadic pheochromocytomas are encapsulated by either a true capsule or a pseudocapsule consisting of the adrenal capsule. Pheochromocytomas are firm in texture. Hemorrhages that occur within a pheochromocytoma can give the tumor a mottled or dark red appearance. Larger tumors frequently have 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 rarely invade adjacent organs; 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.
Table 11-9. Common symptoms in patients with hypertension due to pheochromocytoma.
Paragangliomas are extra-adrenal pheochromocytomas that arise from sympathetic ganglia (Figure 11-8). They account for about 10% of pheochromocytomas in adults and about 30% in children. About 85% are intra-abdominal, where they are typically found in the juxtarenal or para-aortic region, particularly in the perinephric, periaortic, and bladder regions. Retroperitoneal paragangliomas are more likely to be malignant (30–50%) and present with pain or a mass. They tend to metastasize to the lungs, lymph nodes,
and bones. Paragangliomas can be locally invasive and may destroy adjacent vertebrae and cause spinal cord compression. Pelvic paragangliomas may involve the bladder wall, obstruct the ureters, and metastasize to regional lymph nodes. About 36–60% of paragangliomas are functional, secreting norepinephrine and normetanephrine. Functional status is not known to affect survival. Nonfunctional paragangliomas can often concentrate MIBG or secrete chromogranin A. Paragangliomas of the bladder cause symptoms upon micturition. Large perinephric tumors can cause renal artery stenosis. Vaginal tumors can cause dysfunctional vaginal bleeding.
Figure 11-8. Left: Anatomic distribution of extra-adrenal chromaffin tissue in the newborn. Right: Locations of extra-adrenal pheochromocytomas reported before 1965. (Reproduced, with permission, from Coupland R: The Natural History of the Chromaffin Cell. Longmans, Green, 1965.)
Paragangliomas may also arise in the anterior or posterior mediastinum or the heart. Central nervous system locations include the sella turcica, petrous ridge, and pineal region; cauda equina paraganglioma can cause increased intracranial pressure.
Nonchromaffin paragangliomas of neuroectodermal chemoreceptors are known as chemodectomas or glomus tumors; they are typically found in the head and neck, particularly near the carotid body, glomus jugulare, jugulotympanic region, or in the lung. Chemodectomas rarely secrete catecholamines.
Neuroblastomas, ganglioneuroblastomas, and ganglioneuromas are sympathetic nervous system tumors that are related to pheochromocytomas and likewise arise from primitive sympathogonia (Figure 11-1). These neuroblastic tumors account for 10% of childhood cancers. They develop from sympathetic tissue in the adrenal gland neck, posterior mediastinum, retroperitoneum, or pelvis. They differ in their degree of maturation and malignancy. Neuroblastoma tumors derive from immature neuroblasts, are generally aggressive, and tend to occur in very young children.
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. However, individual tumors can behave differently and some neuroblastomas are more indolent, depending upon the nature of their tumor oncogene mutations. Despite catecholamine secretion, children with neuroblastomas tend to be more symptomatic from their metastases than from catecholamine secretion. Tumors tend to concentrate radiolabeled metaiodobenzylguanidine (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. The mortality rate is high for children with neuroblastomas despite recent advances in treatment.
Genetic Conditions Associated with Pheochromocytomas
Most pheochromocytomas occur sporadically, though a substantial proportion of these tumors are found to have developed a somatic mutation similar to those seen in germline mutations that give rise to familial syndromes. Over 10% of pheochromocytomas are hereditary and occur as a feature of certain familial syndromes. Genetic testing is advisable for anyone with a family history of pheochromocytomas, paragangliomas, or bilateral pheochromocytomas. Genetic screening is also performed for patients with other manifestations of genetic syndromes noted below. Such screening can be done for MEN 2 RET oncogene mutations and VHL mutations. Mutations in the newly sequenced genes encoding succinate dehydrogenase subunit B (SDHB) and succinate dehydrogenase subunit D (SDHD) also predispose carriers to develop pheochromocytomas and glomus tumors.
- MULTIPLE ENDOCRINE NEOPLASIA TYPE 2 (MEN 2)
MEN 2 is an autosomal dominant disorder caused by a mutation in the ret proto-oncogene (see Chapter 22). MEN 2 kindreds can be grouped into two distinct subtypes. In either subtype, pheochromocytomas usually develop in the adrenals; extra-adrenal paragangliomas are rare. Patients tend to have hypertension, usually paroxysmal. 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. For example, patients with the 634-point mutation are more prone to develop pheochromocytoma and hyperparathyroidism. Plasma catecholamines may be normal; however, plasma concentrations of metanephrine are elevated early in most patients with pheochromocytomas associated with MEN 2, making this the screening test of choice for these patients.
- MEN 2a (Sipple's syndrome)—Patients with this genetic condition may develop medullary thyroid carcinoma, hyperparathyroidism, pheochromocytoma, or adrenal medullary hyperplasia. Patients with MEN 2a also have a high incidence of lichen planus amyloidosis and Hirschsprung's disease. In patients with an MEN 2a genetic defect, the ultimate occurrence of medullary thyroid carcinoma is nearly 100%. However, the incidence of pheochromocytoma varies in different kindreds, ranging from 6% to 100% (average 40%), depending upon the kindred. Pheochromocytomas tend to present in middle age, often without hypertension. The incidence of hyperparathyroidism has also varied, averaging 35%. Anyone belonging to an MEN 2a kindred should have genetic testing for retproto-oncogene mutations prior to 6 years of age to determine if they
carry the genetic mutation that will require prophylactic thyroidectomy and close surveillance.
- MEN 2b—Patients with this genetic condition are prone to develop aggressive medullary thyroid carcinoma, mucosal neuromas (visible in the eye and mouth), thick corneal nerves, intestinal ganglioneuromas, a marfanoid habitus, and pheochromocytoma or adrenal medullary hyperplasia. In patients with MEN 2b, medullary thyroid carcinoma tends to be aggressive and occurs at an earlier age than in patients with MEN 2a. Anyone belonging to a kindred with MEN 2b should have genetic testing immediately for RET proto-oncogene mutations. If an individual is found to carry the family's proto-oncogene mutation, early prophylactic thyroidectomy is advisable and long-term close surveillance is required.
- VON HIPPEL-LINDAU DISEASE
In von Hippel-Lindau disease, a mutation of the VHL tumor suppressor gene causes an autosomal dominant predisposition to hemangioblastomas in the retina, cerebellum, and spinal cord. About 10–20% of patients with von Hippel-Lindau disease ultimately develop a pheochromocytoma; such patients are usually those having a VHL missense mutation rather than a deletion or frameshift mutation. Kidney cysts, renal cell carcinomas, and pancreatic cysts also occur.
In a French series of 36 patients with pheochromocytomas and von Hippel-Lindau 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 von Hippel-Lindau disease, pheochromocytoma was the only known manifestation.
Plasma normetanephrine levels are usually elevated when patients with von Hippel-Lindau disease develop a pheochromocytoma. Therefore, it is advisable for patients with a VHL gene mutation to be screened regularly with plasma normetanephrine levels; patients with VHLmissense mutations particularly require regular and frequent screening.
- VON RECKLINGHAUSEN'S (TYPE 1) NEUROFIBROMATOSIS (NF-1)
Up to 5% of patients with von Recklinghausen's neurofibromatosis may ultimately develop pheochromocytomas. Such pheochromocytomas can grow to large size. Patients may develop hypertension, but some patients may be 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's disease is caused by a mutation in the NF-1 tumor suppressor gene mapped to chromosome 17q11.2; it is autosomal dominant, though about half of the cases seem sporadic. It is a common condition, with an incidence of 3000 cases per million population. 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. Optic gliomas may affect vision. Patients may also have axillary freckles and multiple cutaneous pigmented café au lait spots that grow in size and number with age; most patients ultimately develop more than six spots measuring > 1.5 cm in diameter.
- FAMILIAL PHEOCHROMOCYTOMAS
Pheochromocytomas may also occur as an isolated familial genetic syndrome. Pheochromocytomas are more likely to be bilateral, and adrenal medullary hyperplasia is common. Individuals with such genetic proclivity require frequent clinical and biochemical screening for pheochromocytoma.
- FAMILIAL PARAGANGLIOMAS
Certain kindreds have a genetic proclivity to develop multicentric extra-adrenal paragangliomas. This syndrome has been attributed to mutations in three genes: SDHB, SDHC, and SDHD.
- CARNEY'S TRIAD
Multicentric paragangliomas occur in patients with Carney's triad. It generally presents in women under age 40 and consists of paragangliomas, indolent gastric leiomyosarcomas, and pulmonary chondromas. (This condition is entirely different from Carney's complex.)
Physiology of Pheochromocytoma & Paraganglioma
Pheochromocytomas are tumors that arise from the adrenal medulla. Paraganglioma is a term used to describe extra-adrenal tumors that arise from nonadrenal chromaffin tissue. 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). This persistent hypersecretion of catecholamines by most pheochromocytomas is probably due to lack of feedback inhibition on tyrosine hydroxylase. Catecholamines are then 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; the excess catecholamines and their metabolites diffuse out of the pheochromocytoma cell into the circulation.
Figure 11-9. Left infrarenal paraganglioma shown by CT scanning. The lower diagram identifies many of the visible structures.
In contrast to the normal adrenal medulla, pheochromocytoma cells ordinarily contain more norepinephrine than epinephrine. In adults, approximately 90% of tumors arise from the adrenal medulla. Pheochromocytomas that secrete epinephrine are particularly likely to be found in the adrenal medulla. Extra-adrenal paragangliomas rarely secrete epinephrine—this is due to their lack of immediate proximity to the adrenal cortex, which ordinarily provides the high concentrations of cortisol needed for induction of the enzyme PNMT, which catalyzes the conversion of norepinephrine to epinephrine.
Surprisingly, the serum levels of catecholamine do not correlate well with tumor size. This appears to be due to the rapid production and secretion of catecholamines by small tumors and the slower secretion of
catecholamines by larger tumors. Furthermore, much of the size of larger tumors is due to hemorrhagic necrosis and cystic formation.
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 serum and urine catecholamines that can occur for 10 days or longer after a successful surgical resection of a pheochromocytoma.
Many pheochromocytomas secrete significant amounts of neuropeptide Y (NPY). NPY is a 36-amino-acid peptide that is a very potent nonadrenergic vasoconstrictor and vascular growth factor.
NPY is found in adrenergic neurosecretory granules and is secreted along with norepinephrine. Patients with essential hypertension have not been found to have elevated levels of NPY. However, in a series of eight patients with pheochromocytomas, NPY levels were elevated twofold 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 measures of vascular resistance, independent of norepinephrine. NPY appears to contribute to hypertension in most patients with pheochromocytoma. In contrast, few paragangliomas secrete NPY.
Neuron-specific enolase (NSE) 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 indicates that a given pheochromocytoma is likely to be malignant.
Secretion of Other Peptides (Table 11-10)
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's syndrome. Secretion of neuropeptide Y contributes to hypertension. Erythropoietin secretion can cause erythrocytosis. Leukocytosis is frequently seen in patients with pheochromocytoma, probably caused by cytokine release from the tumor. IL-6 secretion can cause fevers. Most pheochromocytomas secrete chromogranin A, and serum chromogranin A levels may be assayed as a tumor marker for pheochromocytoma. Pheochromocytomas may also secrete other peptides that are included in Table 11-10.
Table 11-10. Peptides that may be secreted by pheochromocytomas. Pheochromocytomas are variable in their secretion of different peptides. Not all peptides have been documented to produce clinical manifestations. See text.
Manifestations of Pheochromocytoma
- SYMPTOMS OF PHEOCHROMOCYTOMA
Over one-third of pheochromocytomas cause death prior to diagnosis, death being caused by a fatal cardiac arrhythmia or stroke. Adult patients with a pheochromocytoma usually have paroxysmal symptoms, which may last minutes or hours; symptoms usually begin abruptly and subside slowly. Symptoms typically include episodes of headaches (80%), diaphoresis (70%), and palpitations (60%). Other symptoms may include anxiety (50%), a sense of dread, tremor (40%, particularly with epinephrine-secreting tumors), or paresthesias. Recurrent chest discomfort is a frequent complaint. Many patients experience visual changes during acute attacks (Tables 11-8 and 1-9).
Sweating (initially palms, axillae, head, and shoulders) usually occurs. Drenching sweats can occur, usually as a paroxysm subsides. Reflex thermoregulatory eccrine sweating occurs later in an attack, dissipating the heat that was acquired during the prolonged vasoconstriction that occurred during the paroxysm.
Gastrointestinal symptoms predominate in certain patients. Abdominal pain and vomiting are frequent symptoms. The abdominal pain may be due to ischemic enterocolitis. Pain may also be caused by the growth of a large intra-abdominal tumor. Constipation is common, and toxic megacolon may rarely occur.
These 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. Some patients' attacks have been precipitated by nasal decongestants. 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 von Hippel-Lindau disease are especially prone to be normotensive and asymptomatic.
Children with pheochromocytomas or paragangliomas tend to present with a symptom complex that is different from that of adults. Children are more prone to diaphoresis, visual changes, and sustained (rather than episodic) hypertension. Children are more likely to have paroxysms of nausea, vomiting, and headache. They are also prone to weight loss, polydipsia, polyuria, and convulsions. Edema and erythema of the hands occur quite frequently and are rather unique to children with pheochromocytoma. Children are more likely to have multiple tumors and 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.
- SIGNS OF PHEOCHROMOCYTOMA
In adults, hypertension is considered to be present with blood pressures > 140 mm Hg systolic or > 90 mm Hg diastolic. In children, blood pressures increase with age, such that maximal normal ranges are age-dependent; blood pressures at the 95th percentile for age are as follows: < 6 months, 110/60 mm Hg; 3 years, 112/80 mm Hg; 5 years, 115/84 mm Hg; 10 years, 130/92 mm Hg; and 15 years, 138/95 mm Hg.
Hypertension is present in 90% of patients in whom a pheochromocytoma is diagnosed. 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.
Patients with sustained hypertension usually exhibit orthostatic changes in blood pressure. 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 typical of pheochromocytoma. Epinephrine secretion from a pheochromocytoma may cause episodic hypotension and even syncope. Therefore, the determination of orthostatic blood pressure and pulse rate should be a standard component in the evaluation and follow-up of patients with pheochromocytoma. Orthostasis is due to vasomotor adrenergic receptor desensitization; patients may have a diminished intravascular volume.
Left ventricular hypertrophy develops commonly in hypertensive patients with pheochromocytoma. High levels of catecholamines can also cause myocarditis and a dilated cardiomyopathy; full recovery from cardiomyopathy may occur after surgical resection of a pheochromocytoma.
In some patients, myocardial scarring and fibrosis lead to irreversible cardiomyopathy and heart failure. Sudden arrhythmias often occur and may be fatal.
Palpitations are a frequent complaint, and cardiac arrhythmias are common. Sinus 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. As a result of severe peripheral vasoconstriction, the radial pulse can become thready or even nonpalpable during a hypertensive crisis. Vasoconstriction is also responsible for the pallor and mottled cyanosis that can occur with paroxysms of hypertension. Reflex vasodilation usually follows an attack and can cause facial flushing. After an 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.
During pregnancy, a maternal pheochromocytoma can cause sustained hypertension or paroxysmal hypertension that is typically mistaken for eclampsia. Women may suffer from peripartum shock or postpartum fever that can mimic rupture or infection of the uterus.
Most patients lose some weight. 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. Fevers are quite common and 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 IL-6. Distention of the neck veins is common during an attack, and the thyroid may increase in size transiently. Large pheochromocytomas or their metastases may be palpable. Some may grow so large that they impinge on the renal artery, causing renovascular hypertension. Other complications include cerebrovascular accident, malignant nephrosclerosis, and hypertensive retinopathy. Rarely, pheochromocytomas can secrete ACTH in amounts sufficient to stimulate the excessive production of cortisol, with resultant Cushing's syndrome.
About 15% of pheochromocytomas are malignant. Metastases are usually functional and can cause recurrent hypertension and symptoms many months or years after an operation that had been thought to be curative. Metastases can cause a variety of problems. Metastases to the skull are common and are frequently palpable. Therefore, the cranium should be palpated carefully in all patients with pheochromocytomas, particularly when metastases are suspected. Skull metastases can protrude from the cranium as soft masses with a consistency similar to that of sebaceous cysts. Metastases also have a predilection for the ribs, causing chest pain. Metastases to the spine cause back pain or neurologic symptoms due to impingement on the spinal cord or nerve roots. Paragangliomas often arise adjacent to vertebrae and can directly invade them. Pulmonary and mediastinal metastases can cause dyspnea, hemoptysis, pleural effusion, or Horner's syndrome. Metastases involving the thoracic duct can cause chylothorax. Pheochromocytomas may recur within the abdomen as metastases in mesenteric nodes or as masses arising from peritoneal seeding originating from the original tumor. Metastases to the liver can cause hepatomegaly.
- NORMOTENSION DESPITE HIGH PLASMA LEVELS OF NOREPINEPHRINE
Interestingly, many patients with pheochromocytomas and paragangliomas have no hypertension despite having chronically elevated serum levels of norepinephrine. This phenomenon has been variably called desensitization, tolerance, or tachyphylaxis.
Patients can be genetically prone to adrenergic desensitization. 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.
Adrenergic desensitization can also be caused by adrenergic receptors undergoing sequestration, down-regulation, or phosphorylation. Desensitization does not account for all patients who are normotensive in the face of elevated serum levels of norepinephrine; some such patients can still have hypertensive responses to norepinephrine. 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. Adrenergic desensitization also appears to be one cause of the cardiovascular collapse that can occur abruptly following the removal of a pheochromocytoma in some patients.
- CATECHOLAMINES AND METANEPHRINES
The best methodology for assaying catecholamine and metanephrine levels (urine or plasma) has become high-pressure liquid chromatography (HPLC) with electrochemical detection (ECD). This methodology has proved superior to other assays because of its specificity and ease of use. However, misleadingly elevated levels of at least one catecholamine or metanephrine determination occur in up to 10% of patients with essential hypertension. These elevations are typically < 50% above the maximum normal and are usually normal upon retesting while avoiding medications, foods, and
stresses that might cause misleadingly high catecholamine determinations. Patients with pheochromocytomas typically have elevations of catecholamines or metanephrines that are more than twice normal, particularly after a paroxysm.
Urine fractionated catecholamines and fractionated metanephrines are listed in Table 11-11. A single 24-hour urine specimen is collected for the above determinations, plus creatinine. The container is acidified with 10–25 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 (1) assays for fractionated catecholamines, fractionated metanephrines, and creatinine performed on the same specimen; and (2) assay by an endocrine reference laboratory using high-pressure liquid chromatography (HPLC) followed by electrochemical detection.
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, since 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 electrochemical detection) 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 ľg 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.
Plasma catecholamine or metanephrine levels are not usually required. However, since catecholamines are metabolized within tumor cells, plasma levels of free metanephrines and normetanephrines are exceptionally sensitive and can be used as screening tests for pheochromocytoma, particularly when screening for pheochromocytoma in patients with established MEN 2 or von Hippel-Lindau disease. Plasma metanephrine is elevated in most patients with MEN 2, whereas plasma normetanephrine is usually elevated in patients with von Hippel-Lindau disease. Normal ranges for plasma metanephrines in children are different from those of adults and have been reported by Weise et al (see references). Plasma concentrations of norepinephrine do not correlate with blood pressure. Stimulation or suppression tests are not recommended.
There is no single test that is absolutely sensitive and specific for pheochromocytoma. Urinary metanephrines have a sensitivity of about 97%. Sensitivities of other tests are somewhat lower: urinary norepinephrine 93%, plasma norepinephrine 92%, urinary vanillylmandelic acid (VMA) 90%, plasma epinephrine 67%, urinary epinephrine 64%, plasma dopamine 63%.
- SERUM CHROMOGRANIN A
Chromogranin A may be determined by immunoradiometric (IRMA) assays. Chromogranins are acidic glycoproteins that are found in neurosecretory granules. They have been categorized into three classes: chromogranins A (CgA), B (secretogranin I), and C (secretogranin II).
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.
Table 11-11. Maximal normal concentrations of the catecholamines and their metabolism in urine.1 Substances interfering with their measurement are listed.
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. Median morning CgA measurements have been reported to be 43 ng/mL in normals and 34 ng/mL in patients who have bilateral adrenalectomies.
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 malignant pheochromocytoma. In one series, average serum CgA levels were 48 ng/mL in normals, 188 ng/mL in benign pheochromocytoma, and 2932 ng/mL in malignant 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 83–90% 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.
- OTHER LABORATORY TESTS
Measurements of urinary vanillylmandelic acid (VMA) or dopamine have not increased the sensitivity or specificity of pheochromocytoma diagnosis. However, some centers have traditionally used a combination of urinary VMA and metanephrine determinations with good results. Clonidine suppression testing of plasma catecholamines is unnecessary and cumbersome. Glucagon stimulation testing is dangerous and no longer useful. Serum renin levels are not typically suppressed in patients with pheochromocytomas, since catecholamines stimulate renin release and some tumors may secrete renin ectopically.
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/ľL have been reported. Hyperglycemia is noted in about 35% of patients with pheochromocytoma, but frank diabetes mellitus is uncommon. The erythrocyte sedimentation rate (ESR) is elevated in some patients. Hypercalcemia is common and may be caused by bone metastases or tumoral secretion of PTHrP. Erythrocytosis sometimes occurs, caused by 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 now employ high-pressure liquid chromatography (HPLC) with electrochemical detection (ECD). Such assays can be affected by interference from a diverse range of drugs and foods. These substances cause unusual shapes of the peaks on the HPL chromatogram. Not all of these assays are the same, and the potential for interference will depend upon 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 11-12)
Certain radiopaque contrast media can falsely lower urinary metanephrine determinations in some assays for up to 12 hours following administration. Such agents are those that contain meglumine acetrizoate or meglumine diatrizoate (eg, Renografin, Hypaque-M, Renovist, Cardiografin, Urografin, and Conray). 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.
Even using newer HPLC-ECD assay techniques, certain foods can cause misleading results in assays for catecholamines and metanephrines (Table 11-12). Coffee (even if decaffeinated) contains substances that can be converted into a catechol metabolite (dihydrocaffeic acid) that may cause confusing peaks on an HPL chromatogram. 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.
Table 11-12. Factors potentially causing misleading catecholamine or metanephrine results: high pressure liquid chromatography with electrochemical detection (HPLC-ECD).*
Any severe stress can elicit increased production of catecholamines and metanephrines. Diseases causing reduced catecholamine production (Table 11-12) include malnutrition and quadriplegia. Urinary excretion of catecholamines and metanephrines is reduced in renal failure.
Differential Diagnosis of Pheochromocytoma (Table 11-13)
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.
Table 11-13. Differential diagnosis of pheochromocytoma.
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, since 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.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.
The differential diagnosis also includes intracranial lesions, preeclampsia-eclampsia, clonidine withdrawal, hypertensive crisis due to MAO inhibitors, cardiac arrhythmias, unstable angina, hypoglycemia, vascular or cluster headaches, autonomic epilepsy, mastocytosis, acute intermittent porphyria, lead poisoning, encephalitis, and tabetic crisis.
Patients with erythromelalgia can have episodic hypertension, but it is associated with flushing of the face and legs during the attack; patients with pheochromocytoma 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 have 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 will generally show 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.
Neuroblastomas are poorly differentiated malignancies and are the most common solid tumor of childhood. Neuroblastomas may develop in the adrenal gland or in sympathetic nerve ganglia near the cervical or thoracic vertebrae or in the pelvis. They metastasize to bones, lymph nodes, liver, and skin. Cutaneous metastases may present as widespread bluish nodules such that these young patients have been called “blueberry muffin children.” When such nodules are rubbed they tend to blanch, with a ring of surrounding erythema. Neuroblastomas usually present with pain and are often visualized on MRI as “dumbbell lesions”in the neural foramina. About 85% of affected children secrete excessive catecholamines—but rarely in sufficient amounts to cause symptomatic hypotension or the paroxysms typical of pheochromocytomas. Neuroblastomas concentrate 123I-MIBG but can be distinguished from paragangliomas by clinical and histological criteria.
Localization Studies for Pheochromocytoma
- METAIODOBENZYLGUANIDINE (MIBG) SCANNING
Benzylguanidine is a derivative of guanethidine; it is a false neurotransmitter that was initially developed as therapy for hypertension. It was ineffective as an antihypertensive drug but was found to selectively accumulate in cells that store catecholamines in proportion to the concentration of neurosecretory granules. 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 useful also for screening patients for metastases. Interestingly, MIBG uptake does occur in apparently nonfunctioning pheochromocytomas.
The isotope that is preferable for precise imaging is 123I-MIBG, since 123I has a more useful photon flux and lower-energy gamma emissions than 131I, allowing for clearer images and single photon emission computed tomography (SPECT). Additional advantages of 123I include its shorter half-life and reduced heavy particle emissions, resulting in less overall radiation exposure to the patient. 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. However, most centers use 131I-MIBG, since it has a longer half-life than 123I-MIBG and is commercially available. SPECT scanning with radiolabeled MIBG can be combined with simultaneous CT imaging on the same (“Hawkeye”) scanner; the resultant combined images can help distinguish whether a given mass has taken up MIBG.
The overall sensitivity of 123I-MIBG for pheochromocytomas is about 85%; it 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 2a or 2b-related or von Hippel-Lindau disease-related pheochromocytomas.
To block the thyroid's uptake of free radioiodine, saturated solution of potassium iodide, 5 drops orally three times daily, is given before the injection and daily
for several days afterward. The 123I-MIBG is given intravenously, and scanning may be performed between 1 and 3 days thereafter.
- 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 11-14).
- False-positive MIBG scans occur infrequently. Uptake in the normal adrenal medulla and renal pelvis and bladder is commonly seen on day 1 and must be distinguished from tumor uptake. The salivary glands are typically visualized since they are richly innervated. The heart and liver normally take up some 123I-MIBG. Urine contamination with 123I-MIBG can also cause a false-positive scan. 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 on days 2 and 3, preceded by a laxative if required.
- COMPUTED TOMOGRAPHY (FIGURES 11-9, 11-10)
After a pheochromocytoma has been diagnosed by clinical and biochemical criteria, hypertension must first be controlled (see below), since intravenous contrast can precipitate a hypertensive crisis. The pheochromocytoma must then be localized. The first step in locating a pheochromocytoma is to perform a CT scan of the entire abdomen from the diaphragm through the pelvis; thin-section cuts should be obtained through the adrenals.
If urine samples for metanephrines are to be collected within 72 hours following the CT scan, it is important that diatrizoate sodium and not meglumine diatrizoate or acetate be used as the iodinated contrast agent since the former does not interfere with the metanephrine assay. Glucagon should not be used during a CT scan to locate a pheochromocytoma since it may provoke a hypertensive crisis.
Table 11-14. Factors inhibiting MIBG uptake by pheochromocytomas.
If no mass is discovered, a 123I-MIBG scan may be obtained or the CT scan may be extended into the chest and thoracic spine 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 von Hippel-Lindau disease. CT is also less sensitive for detecting extra-adrenal paragangliomas, small metastases, and early recurrent tumors in the adrenal surgical bed.
- MAGNETIC RESONANCE IMAGING (MRI)
MRI does not require intravenous iodinated contrast, thereby minimizing the risk of hypertensive crisis. MRI is the scanning technique of choice during pregnancy because it avoids radiation to the fetus. It can help determine whether an adrenal mass is a pheochromocytoma when biochemical studies are inconclusive. The T2-weighted signal is hyperintense relative to the liver in about 75% of cases. However, some adrenal adenomas may have the same appearance, so the MRI scan lacks true specificity. 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 can visualize and confirm metastases to bone suspected on 123I-MIBG imaging.
- POSITRON EMISSION TOMOGRAPHY (PET)
PET employs certain isotopes that emit positrons during their decay. Positrons are antimatter, so positron-electron collisions occur immediately and produce energy, emitting gamma 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 CT of tumors, which can accurately determine their location and volume. Deoxyglucose is taken up by tissues with active metabolism, including tumors; for PET scanning, it may be tagged with 82Rb or 18F (fluorodeoxyglucose, FDG). [18F]FDG PET scanning can be useful for localizing metastases from a
malignant pheochromocytoma. However, [18F]FDG PET scanning detects other tumors besides pheochromocytoma; it localizes in other tissues having a high metabolic rate, including areas of inflammation, shivering muscles, or other tumors; and it is thus less specific for pheochromocytoma than is 123I-MIBG scanning.
Figure 11-10. Plasma norepinephrine and epinephrine levels in samples of blood from venous sampling. Note that the level of epinephrine is very high in the left adrenal vein sample, distinguishing it from the drainage of the tumor, which secretes mainly norepinephrine into the left renal vein. Note the relatively normal peripheral levels of epinephrine (as seen in the iliac vein or the superior vena cava). Such sampling is rarely required.
PET scanning may also be performed using 6-[18F] fluorodopamine, a technique currently undergoing clinical investigation. It is more specific for paraganglioma and metastatic pheochromocytoma than is [18F]FDG, since dopamine is a substrate for the norepinephrine transporter in tumor tissue.
PET scanning can be done almost immediately, which gives it some advantage over MIBG scanning, which must be delayed for 24–48 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 and has not been directly compared with 123I-MIBG or 131I-MIBG scanning for sensitivity and specificity. The isotope 18F has a half-life of just 2 hours and must be produced in a cyclotron, so [18F]FDG scanning is practical only at medical centers having a cyclotron nearby.
- SOMATOSTATIN RECEPTOR IMAGING (SRI)
Scanning with 111In-labeled octreotide (SRI) has a sensitivity of only 25% for adrenal pheochromocytomas. 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.
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. Without preparatory α-adrenergic blockade, biopsy of pheochromocytomas
has produced hypertensive crisis as well as hemorrhage, resulting in death. Therefore, all patients with an adrenal mass require testing for pheochromocytoma before a biopsy is even considered. When a pheochromocytoma is biopsied, the 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 upon CT scanning and biopsy.
Preoperative Medical Management
Patients need to be treated with oral antihypertensives in order to be relatively stable 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. Prolonged preoperative preparation for longer than 7 days is no more effective for preventing intraoperative hypertension than are shorter preparation times of 4–7 days. In fact, 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 below).
- CALCIUM CHANNEL BLOCKERS
Calcium channel blockers are excellent antihypertensive agents for patients with pheochromocytomas and are preferred in many centers. Patients tend to tolerate calcium channel blockers better than alpha-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 20–40 mg orally every 8 hours; nicardipine is also available as a sustained-release preparation that may be given in doses of 30–60 mg orally every 12 hours. Nifedipine is a similar calcium channel blocker that is administered as a slow-release preparation in doses of 30–60 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. Nifedipine causes a reduction in mitotic index and proliferation of pheochromocytoma cells in vitro; its potential clinical usefulness to reduce tumor growth has not been studied. In one small study, nifedipine therapy appeared to improve the uptake of MIBG into pheochromocytomas in four of eight patients at scanning doses. Another reported therapeutic option is sustained-release verapamil, 120–240 mg orally once daily.
- 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 is given orally in a starting dose of 10 mg daily and increased by 10 mg every 3–5 days until the blood pressure is < 140/90 mm Hg. 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. Patients must be cautioned not to use nasal decongestants if urinary catecholamines or 123I-MIBG scanning is planned, but antihistamines are acceptable. 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 30–60 mg/d, but the dosage is sometimes escalated to as high as 140 mg/d. Excessive alpha blockade with phenoxybenzamine is undesirable since 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 demonstrated effectiveness in the medical management of pheochromocytomas when given orally in doses of 2–16 mg daily. Alternatively, a short-acting selective alpha-blocker (eg, prazosin) appears to cause less reflex tachycardia and less postoperative hypotension. The starting dose of prazosin is 0.5 mg/d, increasing up to 10 mg twice daily if necessary.
- ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS
ACE inhibitors have successfully treated hypertension in patients with pheochromocytomas but not as the sole agent. 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 ACE binding sites. Similarly, angiotensin receptor blockers (ARBs) have been successfully added to multidrug antihypertensive therapy. ACE inhibitors are contraindicated in pregnancy, since 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, since blocking vasodilating β2 receptors without also blocking vasoconstricting α1 receptors can lead to hypertensive crisis if serum norepinephrine levels are high. Even labetalol, a mixed alpha- and beta-blocker, has been reported to cause an unexpected temporary exacerbation of hypertension. Metoprolol is effective. Propranolol, 10–40 mg orally four times daily, is occasionally required. Propranolol crosses the placenta and can cause intrauterine growth retardation. Newborns of mothers taking propranolol at delivery exhibit bradycardia, respiratory depression, and hypoglycemia.
- 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. However, it can be useful as an adjunct with antihypertensive medications to treat patients with uncontrolled hypertension prior to surgery. Metyrosine is administered orally as 250 mg capsules, beginning with one every 6 hours; the dose is titrated upward every 3–4 days according to blood pressure response and side effects. The maximum dosage is 4 g/d. Catecholamine excretion is usually reduced by 35–80%. 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 high-dose 131I-MIBG treatment.
Octreotide has not been formally studied or approved for use in patients with pheochromocytoma. However, octreotide, 100 ľg 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 ľg 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 ľg daily; monthly injections of octreotide LAR may be considered.
- OTHER THERAPIES
Patients with pheochromocytomas may have recurrent fevers caused by tumoral release of interleukin-6 (IL-6). Symptomatic relief may be obtained with nonsteroidal anti-inflammatory drugs such as naproxen.
Surgical Management of Pheochromocytoma
- PREOPERATIVE PREPARATION
Prior to surgery, patients should be reasonably normotensive on medication (see above) and should 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 2 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 (CVP) line helps to 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 is inserted preoperatively to further optimize fluid replacement. Constant
electrocardiographic monitoring is mandatory. Severe hypertension can occur—even in “fully blocked” patients—upon 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 that might be required should be available and in the operating room well in advance.
Anesthetic agents such as intravenous propofol, enflurane, isoflurane, sufentanil, alfentanil, and nitrous oxide appear to be safe and effective. 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.
- ANTIHYPERTENSIVE AND ANTIARRHYTHMIC DRUGS
- Nicardipine is a calcium channel blocker that is an effective antihypertensive agent when administered as an intravenous infusion in doses of 2–6 ľg/kg/min. Nicardipine was successfully used as the sole intraoperative vasodilating agent in one French series of 70 patients and in another series of 19 patients.
- Sodium nitroprusside, given by intravenous infusion, is an effective drug for managing hypertensive episodes; advantages include widespread familiarity with its use and its short duration of action. The usual dose of nitroprusside is 0.3–10ľg/kg/min. High infusion rates should not be given for prolonged periods; long-duration (over 6 hours) nitroprusside infusion rates above 2 ľg/kg/min cause cyanide accumulation to toxic concentrations. Coadministration of sodium thiosulfate (1 g/100 mg nitroprusside) prevents cyanide accumulation.
- Nitroglycerin, given by intravenous infusion, is effective therapy for perioperative hypertension; the required dosage range is 5–100 ľg/min. Since nitroglycerin adheres to polyvinyl chloride tubing, non-PVC infusion sets must be used. Nitroglycerin infusions may 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, 1–2 mg/kg intravenously.
- Phentolamine mesylate is a short-acting α-adrenergic blocker having an intravenous half-life of 19 minutes. It can be given intravenously in bolus doses of 5–15 mg (1–3 mg for children) for blood pressure control. Phentolamine may also be given by intravenous infusion at a rate of 0.5–1 mg/min. Side effects include hypotension, tachycardia, cardiac arrhythmias, nasal stuffiness, nausea, and vomiting.
- Magnesium, given intravenously, has been reported to be effective in managing hypertension during resection of a pheochromocytoma during pregnancy.
- Lidocaine may be used to treat cardiac ventricular arrhythmias; doses of 50–100 mg are given intravenously.
- Atrial tachyarrhythmias may be treated with intravenous atenolol in 1-mg boluses or by constant infusion of esmolol, a short-acting beta-blocker.
- Drugs to avoid include labetalol, atropine, and diazoxide. Labetalol is not recommended for preoperative or intraoperative management of pheochromocytomas since it aggravates postresection hypotension as a consequence of its long half-life. It can also paradoxically initially aggravate hypertension, since its beta-blocking effect may occur initially, allowing a brief period of unopposed alpha receptor stimulation. Labetalol also inhibits MIBG uptake and causes misleading elevations in urinary catecholamine determinations in certain assays.
Atropine should not be used as preoperative medication for patients with pheochromocytomas since it can precipitate arrhythmias and severe hypertension. Diazoxide is not recommended because intravenous boluses can cause profound hypotension.
- 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.
- Laparoscopy—Most pheochromocytomas can be resected by laparoscopy, 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 four subcostal ports of 10–12 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, since 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 versus 7 days). This approach is the least invasive for the patient, who can usually begin eating and ambulating the next day. The laparoscopic approach may also be used during pregnancy. The technique has also been used successfully for certain extra-adrenal paragangliomas. Surgical mortality is under 3% at referral centers.
- Needlescopic adrenalectomy—This procedure uses three subcostal ports of 2–5 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, extensive prior surgical experience with laparoscopy is required.
- Adrenal cortex-sparing surgery—All patients undergoing bilateral total adrenalectomies require lifelong glucocorticoid and mineralocorticoid hormone replacement. In order 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%.
- Open laparotomy—Open laparotomy is indicated for patients with particularly large pheochromocytomas or for those with intra-abdominal metastases that require debulking. An open anterior midline or subcostal approach usually yields adequate exposure.
- THERAPY OF 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 & Pheochromocytoma
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. 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 is also useful. The tumor is resected after delivery.
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. Nifedipine is tolerated and preferred.
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.
Malignant Pheochromocytoma & Paraganglioma
Metastases are evident at the time of diagnosis in about 10% of patients with an adrenal pheochromocytoma. Another 5% are found to have metastatic disease within
5–20 years. Patients with MEN have been found to have a higher risk that a pheochromocytoma will be malignant. Paragangliomas are commonly malignant (30–50%).
Metastases can often be detected at the time of initial discovery of the pheochromocytoma or paraganglioma. Metastases are usually evident on the initial CT or MIBG procedure. Neither histopathologic examination nor endocrine testing can reliably determine whether a given pheochromocytoma is benign or malignant. The risk of malignancy is higher under the following circumstances: extra-adrenal location, larger size (6 cm or more in diameter), confluent tumor necrosis, vascular invasion, or extensive local invasion. Tumors having a high c-mycmRNA expression are also more likely to be malignant. In one series, 50% of patients with malignant pheochromocytoma were found to have high serum levels of neuron-specific enolase (NSE), but in none of 13 patients in another series with benign pheochromocytomas was there high NSE.
Serum neuropeptide Y (NPY) levels tend to be higher in malignant than in benign pheochromocytomas, but NPY has not proved helpful in making the diagnosis of malignancy. Malignancy is really determined only by the presence of metastases, which may be detected on whole-body 123I-MIBG, 111In-octreotide, PET, or CT scanning of the abdomen, pelvis, and chest. Patients must be followed closely after resection of an apparently benign pheochromocytoma, since metastases may require 20 years or more to become apparent. Urinary norepinephrine or normetanephrines 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, since small or nonsecretory metastases may still be present.
The differential diagnosis for apparent metastases includes benign paragangliomas, multicentric paragangliomas, second pheochromocytomas, intraperitoneal seeding during surgery, and false-positive 123I-MIBG scanning. Malignant pheochromocytomas typically metastasize to bones, lymph nodes, liver, the contralateral adrenal, the lungs, and sometimes to brain or muscle (Table 11-15). The bones most frequently involved include vertebrae, pelvis and ischium, clavicles, and proximal femurs and humeri; metastases to the cranium occur frequently, having a predilection for the frontal bone. Prevertebral paragangliomas may destroy adjacent vertebrae, and spinal cord compression may occur. The 5-year survival for patients with metastatic disease is about 50%. However, patients with multiple pulmonary metastases generally have a poorer prognosis.
It is usually best to surgically resect the primary tumor as well as large metastases. CT scans may not visualize small malignant intra-abdominal metastases that are visualized with preoperative 123I-MIBG scanning. In such cases, following preoperative injection of 123I-MIBG, the surgeon may be able to locate small tumors with the intraoperative use of a portable gamma probe. Hypertension must be adequately controlled.
Table 11-15. Distribution of metastases in 41 cases of malignant pheochromocytoma.1
Chemotherapy has been administered to patients with metastatic pheochromocytomas or paragangliomas. One reported chemotherapy regimen uses cyclophosphamide, vincristine, and dacarbazine (CVD); this chemotherapy regimen, given to 12 patients every 21 days, caused complete or partial remissions in 57%. For metastatic paraganglioma, a regimen of cyclophosphamide, doxorubicin, and dacarbazine has caused partial remission or stabilization in most patients. However, tumors usually relapse after cessation of chemotherapy. Chemotherapy has successfully caused temporary clearing of bone marrow metastases in preparation for stem cell harvest before therapy with high-dose 131I-MIBG (see below).
External beam radiation therapy is administered to symptomatic metastases in the spine, long bones, or central nervous system. When administered to patients with symptomatic spinal or cranial metastases, radiation therapy can reduce pain and produce neurologic improvement. However, pheochromocytomas are relatively resistant to conventional radiation therapy. Radiation therapy to large primary tumors or intra-abdominal metastases is not advisable, since 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. Therefore, surgical debulking of large abdominal or
thoracic tumors (or other therapies) is usually preferable to radiation therapy.
131I-MIBG treatment was first given to patients with malignant pheochromocytomas in 1983 at the University of Michigan. Subsequently, many other patients have been treated with this agent. Most treatment protocols employ repeated doses up to 200 mCi (7.4 GBq). Uptake occurs in many nonfunctioning pheochromocytomas and metastases, and such treatment can therefore be effective for such nonfunctioning tumors if 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 is being given to patients with metastatic pheochromocytomas under a phase II treatment protocol at the University of California San Francisco. Precautions that must be taken before therapy include bone marrow biopsy to ensure absence of tumor in the marrow; granulocyte colony-stimulating factor-stimulated stem cell leukapheresis is then performed and cells cryopreserved for use in the event of prolonged marrow suppression. Patients are medicated with potassium iodide and potassium perchlorate to reduce the risk of thyroid damage that could be caused by any free 131I generated through metabolism of 131I-MIBG. The patient receives an intravenous infusion of 131I-MIBG at a dose of up to 18 mCi/kg to a maximum of 800 mCi (29.6 GBq) over about 2 hours. Patients remain hospitalized until the emitted gamma radiation declines to acceptable levels, which usually requires about 5–7 days.
Most patients receiving 131I-MIBG therapy achieve partial remission, stable disease, or symptomatic relief. Complete remissions are uncommon and have usually occurred in patients with a light tumor burden. Therapy with high-dose 131I-MIBG appears to improve 5-year survival. High doses tend to cause temporary nausea; long-term risks include bone marrow suppression, infertility, and a projected slight increase in the lifetime risk of second malignancies. Repeated treatments may be required.
The mortality rate for patients undergoing pheochromocytoma resection has dropped to under 3% thanks to better medical preparation and surgical techniques. Laparoscopic surgical techniques reduced perioperative morbidity and have shortened the length of hospitalization. However, even after complete resection of the pheochromocytoma, hypertension persists or recurs in 25%. Recurrent hypertension is an indication for reevaluation for pheochromocytoma.
Patients with benign pheochromocytomas 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. Patients with metastatic pheochromocytomas have a 5-year survival rate of only 44%; those with diffuse pulmonary metastases have an even poorer prognosis. The survival of patients with metastatic disease can be improved by intensive blood pressure control and aggressive resection of the primary tumor and metastases. Metastatic and recurrent pheochromocytomas and paragangliomas vary greatly in their aggressiveness. Some metastatic or recurrent tumors are indolent or slow-growing, and prolonged survival has been reported. The symptoms and survival rate for patients with MIBG-avid metastases may also be improved with 131I-MIBG therapy.
All patients with pheochromocytomas require close follow-up. Persistent symptoms or hypertension can signify lack of cure and 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 probably caused by tumor seeding that may occur spontaneously from the original tumor or during surgery.
Patients are followed with 24-hour urine collections for fractionated catecholamines, metanephrines, and creatinine. The first postoperative urine collection for fractionated catecholamines, metanephrines, and creatinine is obtained at least 2 weeks after surgery since catecholamine excretion often remains high for up to 10 days after successful surgery (see above). Quarterly urine collections are obtained 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 renal function is normal; elevated and rising levels of CgA usually indicate tumor recurrence or metastases. Nonfunctioning tumors may later develop functioning metastases. Lifetime medical follow-up is required.
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 123I-MIBG 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 first postoperative scan is usually obtained several months after surgery. Follow-up 123I-MIBG scanning is particularly useful for patients with malignant or nonsecreting pheochromocytomas.
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Medical Therapy for Pheochromocytoma
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