Tumors of the Sympathoadrenal System
Tumors of the sympathoadrenal system include pheochromocytomas, paragangliomas, ganglioneuromas, ganglioneuroblastomas (GNBs), and neuroblastomas (NBs). These tumors arise from primitive sympathoadrenal cell precursors in the neural crest (Fig. 5.1) which differentiate into mature adrenal chromaffin cells, extra-adrenal chromaffin cells, and sympathetic ganglion cells. At each stage of maturation, transformation into tumors may occur as shown in Figure 5.1.
Pheochromocytoma
The chromaffin cell
Pheochromocytoma, by far the most clinically important of the group of sympathoadrenal tumors, arise from chromaffin cells, principally in the adrenal medulla, but also in extra-adrenal locations. The portmanteau term chromaffin implies an affinity for chromium salts, derived from the fact that the cut surface of the adrenal medulla darkens markedly on exposure to potassium dichromate; the dichromate oxidizes the catecholamines which polymerize to highly pigmented compounds that turn the tissue black (Fig. 5.2) when applied to the cut surface of the tumor. Formerly used in confirming the diagnosis, it has been replaced by identifying neuroendocrine markers and by the characteristic electron photomicrograph appearance which clearly demonstrates chromaffin granules. Extra-adrenal pheochromocytomas are also called paragangliomas (Fig. 5.1). Some tumors arising from parasympathetic ganglia, particularly in
the head and neck, do not secrete catecholamines but are also referred to as paragangliomas. The term “pheo” is just a shortened, convenient designation for pheochromocytoma.
the head and neck, do not secrete catecholamines but are also referred to as paragangliomas. The term “pheo” is just a shortened, convenient designation for pheochromocytoma.
 FIGURE 5.1. Genesis of tumors derived from the sympathoadrenal system. |
 FIGURE 5.2. The gross appearance of pheochromocytoma ranges from pink–tan to yellow to slightly brown. The freshly cut tumor surface turns dark brown (right half of image) when immersed in potassium dichromate solution (pH between 5 and 6). This is caused by oxidation of stored catecholamines synthesized by the tumor and is known as the chromaffin reaction. (From the University of Alabama at Birmingham Department of Pathology PEIR Digital Library© [http://peir.net].) |
Incidence and importance
Pheochromocytoma is an uncommon disease: it has been estimated that between 0.1% and 0.2% of the hypertensive population harbors a pheochromocytoma. Even so, given the prevalence of hypertension, the incidence of undiagnosed
patients with pheochromocytoma is not insignificant. In fact, unselected autopsy series indicate that a great majority of pheochromocytomas are not diagnosed during life, even though the tumor is responsible for the death in most of these cases. The relative rarity of pheochromocytoma, therefore, should not obscure its importance: promptly diagnosed and properly treated pheochromocytoma is usually completely curable; if the diagnosis is missed, or if the disease is improperly treated, death is the usual outcome.
patients with pheochromocytoma is not insignificant. In fact, unselected autopsy series indicate that a great majority of pheochromocytomas are not diagnosed during life, even though the tumor is responsible for the death in most of these cases. The relative rarity of pheochromocytoma, therefore, should not obscure its importance: promptly diagnosed and properly treated pheochromocytoma is usually completely curable; if the diagnosis is missed, or if the disease is improperly treated, death is the usual outcome.
The clinical manifestations of pheochromocytoma are due to the unregulated release of catecholamines from the tumor. As a consequence, alarming and occasionally catastrophic signs and symptoms can occur, obscuring the diagnosis, and confounding proper management. In some cases, other biologically active compounds may be released, producing distinctive clinical manifestations (Table 5.1).
Pheochromocytoma is usually solitary and sporadic but a significant minority of patients have pheochromocytoma as part of an inherited syndrome. In these cases, bilateral, multiple, and extra-adrenal tumors frequently occur.
Location
In adults, about 80% of pheochromocytomas are sporadic, solitary, nonmalignant tumors located in or about a single adrenal, 10% are bilateral, 10% are extra-adrenal, and about 10% are malignant. In children, bilateral and extra-adrenal pheos are more common than in adults. Bilateral adrenal pheochromocytomas always indicate an inherited syndrome and necessitate genetic screening. Extra-adrenal pheos are located in or about the sympathetic ganglia and reflect the embryonic location of extra-adrenal chromaffin cells (Fig. 5.3). Most occur within the abdomen around the preaortic plexuses including the celiac, the superior mesenteric, and the inferior mesenteric ganglia. About 10% of the extra-adrenal pheos occur in the thorax usually around the paraspinal sympathetic ganglia. One percent are located in the urinary bladder. Approximately 3% may be found in the head
and neck either with the sympathetic ganglia or the extracranial branches of the 9th or 10th cranial nerves, although these rarely secrete catecholamines. Isolated case reports indicate that pheochromocytomas may occur in a variety of other locations within viscera.
and neck either with the sympathetic ganglia or the extracranial branches of the 9th or 10th cranial nerves, although these rarely secrete catecholamines. Isolated case reports indicate that pheochromocytomas may occur in a variety of other locations within viscera.
TABLE 5.1 Peptide Hormones Produced and Secreted by Pheochromocytomas | ||||||||||||||||||
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 FIGURE 5.3. Distribution of chromaffin tissue in the newborn compared with the distribution of extra-adrenal pheochromocytomas. Extra-adrenal pheochromocytomas (right) occur in sites containing chromaffin tissue in the newborn (left). (From Landsberg L, Young JB. Williams Textbook of Endocrinology. Philadelphia, PA: WB Saunders; 1992:621-705.) |
Pathology
Pheochromocytomas are very vascular. As such, they are subject to hemorrhage and necrosis, as seen on the cut surface of these tumors (Figs. 5.2 and 5.4). Necrosis in the tumor leads to release of stored catecholamines resulting in the paroxysm that characterizes pheochromocytoma; the surgical specimen frequently shows a fresh hemorrhage, presumably responsible for the hypertensive crisis that brought the patient to medical attention.
 FIGURE 5.4. Adrenal pheochromocytoma showing cut surface. The marker is 1 cm. Note the normal adrenal surrounding the tumor, and extensive hemorrhage and necrosis. (From Landsberg L, Young JB. Williams Textbook of Endocrinology. Philadelphia, PA: WB Saunders, 1992:621-705.) |
Most adrenal pheochromocytomas weigh less than 100 g and are less than 10 cm in diameter, but very large tumors, softball size, occasionally occur. Extra-adrenal pheos are typically smaller weighing between 20 and 40 g and measuring less than 5 cm in diameter.
Microscopically, pheos consist of large pleomorphic chromaffin cells containing chromaffin granules strikingly demonstrated by electron microscopy. They stain positive for chromogranin A and other markers indicative of a neural origin such as synaptophysin and tyrosine hydroxylase. Malignancy occurs in less than 10% of pheos overall; extra-adrenal pheos that are part of genetic paraganglioma (PGL) syndromes are more likely to be malignant. Malignancy cannot be determined by the histologic features or even by local invasion; distant metastases are the only sure measure of malignancy but a variety of features suggesting aggressiveness have been described such as high cellularity, confluent necrosis, vascular invasion, aneuploidy or tetraploidy, and an increase in mitotic figures. Metastases, when these occur, are found in lymph nodes, bone, liver, and lung.
Catecholamine storage and release
The synthesis and storage of catecholamines in pheochromocytomas resemble those same processes that occur in the normal adrenal medulla. The mechanisms of release of these compounds from the tumor, however, are poorly understood because pheochromocytomas, unlike the normal adrenal medulla, are not
innervated. It seems likely that necrosis, changes in blood flow, and external pressure may be involved in triggering release. A number of drugs used therapeutically and diagnostically have the capacity to stimulate release from the tumor, occasionally with catastrophic results, as described below.
innervated. It seems likely that necrosis, changes in blood flow, and external pressure may be involved in triggering release. A number of drugs used therapeutically and diagnostically have the capacity to stimulate release from the tumor, occasionally with catastrophic results, as described below.
Adrenal pheos produce both NE and E, with the percentage of NE generally exceeding that found in the normal adrenal medulla. This is reflected in the urinary catecholamine excretion pattern: NE is most commonly the predominant catecholamine excreted. An important exception is in the multiple endocrine neoplasia type 2 (MEN 2) syndromes described below. In these cases, E predominates and early on elevated urinary E is the only abnormality. Extra-adrenal pheochromocytomas secrete NE exclusively with the vanishingly rare exception of extra-adrenal tumors that contain phenylethanolamine-n-methyltransferase (PNMT) and produce E as well as NE. The predominant catecholamine secreted cannot be predicted from the constellation of symptoms. Increased secretion of dopamine (DA) or its major metabolite homovanillic acid (HVA) is much more common in malignant than the usual benign tumor, although increased DA exertion is not diagnostic of malignancy.
Other bioactive compounds released from pheochromocytomas
Pheos produce and secrete a variety of hormones and mediators that may contribute to the clinical presentation (Table 5.1). Most notable and clinically relevant are corticotropin (adrenocorticotropic hormone—ACTH), adrenomedullin, parathyroid hormone-related protein (PTHrP), vasoactive intestinal peptide (VIP), erythropoietin, and interleukin-6 (IL-6).
Typical clinical features
The clinical manifestations of pheochromocytoma reflect the unrestrained release of catecholamines and other bioactive substances from the tumor.
The paroxysm is the defining feature of pheochromocytoma (Table 5.2). Episodic headache, sweating, and palpitations constitute the classic symptom triad. The typical pressor crisis or paroxysm occurs as a presenting manifestation in about half the patients with pheochromocytoma. If the blood pressure is taken during one of these episodes, it will almost always be elevated, often to alarming levels. The opportunity to observe and record the BP during a symptomatic episode has, therefore, significant diagnostic importance.
Paroxysms last from minutes to hours and occur at variable intervals, although as the disease progresses, they tend to occur more frequently and to be more severe. In addition to the classic triad of headache, palpitation, and sweating, chest or abdominal pain with nausea and vomiting are common. Pallor or flushing may be associated. The abdominal pain may be severe and frequently reflects hemorrhage within the tumor; hemorrhagic necrosis is frequently responsible for the catecholamine release that causes the crisis.
Although the paroxysm is the most distinctive feature of pheo, hypertension is the most common clinical manifestation, occurring in almost all cases that are
diagnosed clinically. The hypertension is sustained in about 60% of patients with pheochromocytoma; in the remainder, it is episodic, occurring mostly during paroxysms (Table 5.3).
diagnosed clinically. The hypertension is sustained in about 60% of patients with pheochromocytoma; in the remainder, it is episodic, occurring mostly during paroxysms (Table 5.3).
TABLE 5.2 The Typical Paroxysm | ||||||||||||||||||||||||
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As about half the patients with a pheo do not have discreet spells or paroxysms, it is useful to consider when pheo should be suspected in hypertensive patients (Table 5.4). This is important because pheo patients with sustained high blood pressure and no paroxysms masquerade as essential hypertension. There are, however, clues that suggest the need to rule out pheochromocytoma in hypertensive patients. These include: hypertension of new onset; young age; very high BP; malignant hypertension defined by fibrinoid necrosis of arterioles manifesting clinically as flame hemorrhages in the eye grounds, retinal infarctions (cotton wool spots), and heavy proteinuria and/or hematuria; incidental adrenal mass on imaging; recent weight loss; tachycardia; high hematocrit; marked BP lability; new carbohydrate intolerance; and when orthostatic hypotension is present in the untreated state. As pheochromocytoma is a rare disease, it will need to be excluded much more often than ruled in. The consequences of missing the diagnosis, as noted above, are grave.
TABLE 5.3 Hypertension in Pheochromocytoma | ||||||||||||||
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TABLE 5.4 Features in Hypertensive Patients That Warrant Screening for Pheochromocytoma | |||||||||||||
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Other distinctive clinical features and underlying pathophysiology
The orthostatic hypotension, frequently noted in patients with pheo, is due principally to venoconstriction and diminished plasma volume (Table 5.5). The body cannot assess volume status directly but is very good at measuring changes in pressure; the surrogate measure for volume, pressure in the capacitance portion of the circulation (great veins) is, therefore, the afferent signal for changes in volume. Under ordinary circumstances, an increase in pressure in the great vein signifies volume expansion (“a full tank”) and initiates a diuresis to maintain extracellular fluid balance. Catecholamine-stimulated venoconstriction in patients with a pheo increases pressure in the venous system, thereby simulating volume expansion and initiating a diuresis which results in decreased plasma volume. Rather than a “full tank,” patients with a pheo have a smaller tank. The decreased plasma volume impairs the normal physiologic response to upright posture, which entails maintaining venous return by shifting blood from the capacitance vessels to the heart thus maintaining cardiac output.
An additional contributing factor to the orthostatic fall in BP may be the loss of reflex tone in the SNS because of the high circulating catecholamine levels.
Carbohydrate intolerance is common in patients with pheo and overt diabetes mellitus is not rare; the major factor responsible is suppression of insulin by the direct effect of catecholamines on the pancreatic beta cells. Alpha adrenergic blockade will release the restraint on insulin and restore carbohydrate metabolism toward normal in most cases. Surgical removal frequently reverses the impairment in carbohydrate resulting in a “cure” of the diabetes.
Increased metabolic rate in pheochromocytoma patients is another common pathophysiologic manifestation. The stimulation of thermogenesis results in sweating, not fever, as the temperature set point is not altered. Weight loss is
common in pheo patients because of the increased thermogenesis. The old adage “forget a fat pheo” is based on this propensity toward weight loss; pheo does occur in obese patients but generally they will have lost weight prior to initial presentation. Fever occurs in a small minority of patients because of the production of IL-6 by the tumor.
common in pheo patients because of the increased thermogenesis. The old adage “forget a fat pheo” is based on this propensity toward weight loss; pheo does occur in obese patients but generally they will have lost weight prior to initial presentation. Fever occurs in a small minority of patients because of the production of IL-6 by the tumor.
TABLE 5.5 Some Other Manifestations of Pheochromocytoma | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Cardiac manifestations are also common in pheo patients. Cardiac ischemia, manifested by typical angina due to increased myocardial oxygen demand (↑ BP, ↑contractile state, ↑wall tension) and/or transmural infarction secondary to coronary artery spasm have been noted. Coronary spasm is inferred from normal coronary arteries at angiography in the face of a transmural infarct. Congestive heart failure secondary to hypertension, cardiac hypertrophy, and catechol-amine-induced myocardial fibrosis also occurs. A variety of arrhythmias and conduction disturbances have also been noted.
A high hematocrit may be present, reflecting either reduced plasma volume (“stress” polycythemia from venoconstriction) or, less commonly, actual erythrocytosis from ectopic erythropoietin production. Hypercalcemia may also occur
due to the production of PTHrP. The incidence of cholelithiasis is increased as well in pheochromocytoma patients. Intense vasoconstriction may cause muscle necrosis (rhabdomyolysis) or ischemic colitis.
due to the production of PTHrP. The incidence of cholelithiasis is increased as well in pheochromocytoma patients. Intense vasoconstriction may cause muscle necrosis (rhabdomyolysis) or ischemic colitis.
Rarely, IL-6 production by the pheo results in an acute and sometimes recurrent, systemic inflammatory response syndrome. Associated symptoms include fever, chills, headache, shortness of breath, leukocytosis, and increased levels of inflammatory markers.
Presentation of pheochromocytoma
Pheochromocytoma may present in a variety of ways that suggest other diseases, thereby obscuring the correct diagnosis (Table 5.6). The two most common presentations are hypertension and spells (paroxysms) suggesting essential hypertension on the one hand and panic attacks or epilepsy on the other. Another common presenting manifestation is an unusual blood pressure response (either up or down) to therapeutic or diagnostic interventions. It is said that one out of 20,000 general anesthesias uncovers an unsuspected pheo. Fentanyl, in particular, widely used as a preanesthetic medication, has been well documented to induce a paroxysm, and occasionally these have been fatal. Other less common modes of presentation include: an adrenal mass on imaging for some other indication (adrenal incidentaloma); severe hypotension with noncardiogenic pulmonary edema (shock lung); an abdominal catastrophe with pain and shock (hemorrhage into the tumor); and screening of asymptomatic persons within a kindred of syndromic pheochromocytoma (described in subsequent sections).
Based on autopsy series of consecutive cases of pheochromocytoma from the Mayo Clinic, the majority of cases of pheochromocytoma were not suspected clinically and many were asymptomatic or manifested only nonspecific symptoms.
Adrenal “incidentalomas”
Adrenal incidentalomas are lesions of 1 cm or more discovered incidentally on imaging the abdomen. The prevalence is about 4% on average as judged from
autopsy and computed tomography (CT) studies; they occur more commonly in the elderly. About 5% of adrenal incidentalomas turn out to be pheochromocytomas. Although phenotypic appearance on imaging may suggest that pheo is more or less likely, expert consensus favors ruling out pheochromocytoma in all incidentaloma patients before diagnostic tests, such as fine needle aspiration, are performed. This is best achieved by measuring fractionated catecholamines and metanephrines in a 24-hour urine specimen, as described below.
autopsy and computed tomography (CT) studies; they occur more commonly in the elderly. About 5% of adrenal incidentalomas turn out to be pheochromocytomas. Although phenotypic appearance on imaging may suggest that pheo is more or less likely, expert consensus favors ruling out pheochromocytoma in all incidentaloma patients before diagnostic tests, such as fine needle aspiration, are performed. This is best achieved by measuring fractionated catecholamines and metanephrines in a 24-hour urine specimen, as described below.
TABLE 5.6 The Many Presentations of Pheochromocytoma | ||||||||||
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Adverse drug interactions
Adverse drug reactions are responsible for significant morbidity and mortality in patients with pheochromocytoma; in many instances, these reactions trigger a life-threatening paroxysm that leads to the diagnosis (Table 5.7). The adverse drug reactions in pheo patients are of three major types: direct release of catecholamines from the tumor; impairment in catecholamine inactivation; and release of catecholamines from augmented tissue stores in sympathetic nerve endings. Of these, by far the most significant and the most dangerous are the agents that directly release catecholamines from the tumor. Of the latter group, opioids are the most important and arguably among the least appreciated offenders.
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