Pheochromocytomas are the main pathological entity of the adrenal medulla. Other tumors of the adrenal medulla or its embryonic precursors include neuroblastomas and ganglioneuromas. Neuroblastomas are one of the most common tumors of early childhood. In response to therapy (or even spontaneously), neuroblastomas can differentiate into ganglioneuromas. Both of these tumors secrete catecholamines, but symptoms due to catecholamine excess are usually absent because they do not reach the levels observed with pheochromocytomas. Absence of the adrenal medulla (eg, after bilateral adrenalectomy) is usually well tolerated, though sometimes symptoms such as orthostatic hypotension may be observed. Closely related, but different from pheochromocytomas, are parasympathetic nervous system paragangliomas, which often arise in the affected patient’s head and neck area.
Pheochromocytomas are neoplasms of the chromaffin cells of the adrenal medulla or extramedullary sites. These tumors secrete excessive amounts of epinephrine, norepinephrine, or both (rarely dopamine). Most pheochromocytomas secrete norepinephrine and cause sustained or episodic hypertension. Pheochromocytomas that secrete epinephrine cause hypertension less often; more frequently, they produce episodic hyperglycemia, glucosuria, and other metabolic effects.
Table 12–2 summarizes the clinical features of pheochromocytomas. Pheochromocytomas are uncommon, probably found in less than 0.1% of all patients with hypertension and in approximately two individuals per million population. Pheochromocytomas occur in both sexes and in all age groups but are most often diagnosed in the fourth or fifth decade of life. Compared with adults, children with pheochromocytomas are more likely to have multifocal and extra-adrenal tumors, and a causal familial syndrome must always be excluded.
Table 12–2Clinical features of pheochromocytoma. ||Download (.pdf) Table 12–2 Clinical features of pheochromocytoma.
|Epidemiology ||Adults; both sexes; all ages, especially 30–50 years |
|Biologic behavior ||90% benign; 10% malignant |
|Secretion ||High levels of catecholamines; most secrete norepinephrine |
|Clinical presentation ||Sustained or episodic hypertension, sweating, palpitations, hyperglycemia, glycosuria |
| ||Occasionally asymptomatic (found incidentally on CT scan or MRI) |
|Macroscopic features ||Mass, often hemorrhagic; 10% bilateral, 9–23% extra-adrenal |
|Microscopic features ||Nests of large cells, vascular stroma |
The diagnosis is important because sudden release of catecholamines from these tumors during anesthesia, surgery, or obstetric delivery may prove fatal. Pheochromocytoma was classically referred to as “the 10% tumor” because 10% occur in extra-adrenal paraganglia, 10% are outside the abdomen, 10% are multiple, 10% are bilateral, about 10% are not associated with hypertension, 10% occur in children, and 10% are malignant. Recent research has revised some of these numbers. So, previously, it was thought that about 10% occur as part of a familial syndrome, but now it appears that actually about 20–30% of cases are familial. Also, occurrence at extra-adrenal sites seems to be higher (9–23%) and multifocal pheochromocytomas can be found in roughly one third of childhood cases.
Several genetic syndromes, all transmitted in an autosomal dominant fashion, are associated with an increased risk of pheochromocytoma and sympathetic or parasympathetic nervous system paragangliomas. Most familial cases are caused by one of four syndromes: neurofibromatosis type 1, von Hippel–Lindau syndrome, multiple endocrine neoplasia type 2 (MEN-2), and familial paraganglioma syndrome (Table 12–3). The genetic basis of these syndromes is now well defined. Patients with neurofibromatosis type 1 (von Recklinghausen disease) have an increased incidence of pheochromocytoma caused by mutation of the NF1 gene. Pheochromocytoma is a frequent occurrence in families with von Hippel–Lindau disease, which is caused by mutations of the VHL tumor suppressor gene. VHL-associated pheochromocytomas often secrete norepinephrine.
Table 12–3Major genetic syndromes associated with pheochromocytoma. ||Download (.pdf) Table 12–3 Major genetic syndromes associated with pheochromocytoma.
|Syndrome ||Clinical Features ||Pheochromocytomas/Paragangliomas ||Gene ||Locus |
|MEN-2A ||Medullary thyroid carcinoma ||50% develop pheochromocytoma || RET ||10q11.2 |
| ||Parathyroid hyperplasia ||Bilateral, asynchronous pheochromocytoma || || |
| ||Pheochromocytoma || || || |
|MEN-2B ||Medullary thyroid carcinoma || || || |
| ||Pheochromocytoma || || || |
| ||Ganglioneuromas || || || |
| ||Marfanoid habitus || || || |
|NF-1 ||Neurofibromas ||0.1–5.0% develop pheochromocytoma (20–50% of hypertensive patients) || NF1 ||17q11.2 |
| ||Café-au-lait spots || || || |
| ||Lisch nodules ||90% benign || || |
| ||Plexiform neurofibromas || || || |
| ||Sphenoid dysplasia ||10% bilateral || || |
| ||Optic gliomas || || || |
| ||Axillary and inguinal freckling ||6% extra-adrenal || || |
| ||Pheochromocytoma || || || |
|VHL ||Hemangioblastomas (brain, spine, retina) ||20% develop pheochromocytoma || VHL ||3p26-25 |
| ||Clear-cell renal cell cancer || || || |
| ||Pheochromocytoma || || || |
|PGL1-4 ||Paraganglioma (parasympathetic or sympathetic) ||30% of SDHB pheochromocytoma/paraganglioma, malignant || PGL1-SDHD ||3p26-25 |
| ||Pheochromocytoma || || PGL3-SDHC || |
| || || || PGL4-SDHB || |
In MEN-2A syndrome, pheochromocytomas occur in association with calcitonin-producing medullary carcinoma or C-cell hyperplasia of the thyroid and parathyroid hormone (PTH)–producing adenomas of the parathyroid. In MEN-2B, pheochromocytomas occur in association with medullary carcinoma of the thyroid and numerous oral mucosal neuromas. About 50% of patients with MEN-2A and MEN-2B have pheochromocytomas, often bilaterally. The gene responsible for MEN-2A and MEN-2B has now been localized to chromosome 10q11.2. The position of the RET mutation is related to disease phenotype. Any mutation of the RET proto-oncogene at one specific position (codon 634) is associated with MEN-2A and mutations at a different position (codon 918), with MEN-2B. These germline mutations of the RET proto-oncogene were the first examples of a dominantly acting oncogenic point mutation found to cause a heritable neoplasm in humans. These missense mutations can be detected by DNA analysis, allowing identification of MEN carriers.
The most prevalent change involves a cysteine residue in position 634 of the RET proto-oncogene. RET encodes a plasma membrane–associated tyrosine kinase that associates with a number of different related receptors. When these receptors are activated, they dimerize and bring two molecules of the RET tyrosine kinase close together, which initiates the cellular transmission of the signal. The 634 cysteine residue is part of an intramolecular sulfide bridge between associated cysteine residues. When one cysteine is absent, two RET molecules form intermolecular bridges, resulting in the initiation of intracellular signaling even in the absence of receptor association or ligand activation.
Familial paraganglioma syndromes are transmitted in autosomal dominant fashion and are caused by germline mutations in genes coding for subcomponents of the succinate-dehydrogenase complex (SDHD, SDHB, SDHC, and rarely SDHA and SDHAF2). Extra-adrenal paragangliomas of the abdomen (SDHB) and head and neck area (SDHD and SDHC) are more common in patients with familial paraganglioma. SDHD mutations are influenced by genomic imprinting causing a “parent of origin effect.” Affected patients always inherit the defective allele from their father. Indeed, while a carrier of a maternally inherited allele can propagate the defect to offspring, this mutant allele does not increase the risk for a paraganglioma.
SDHx and VHL mutations both cause perturbations in the same intracellular signaling cascade that is usually induced by hypoxia, causing a “pseudo-hypoxia” state. SDHx mutations lead to an accumulation of succinate, which in turn inhibits an enzyme that hydroxylates the transcription factor hypoxia-induced factor α (HIF1α.) Hydroxylated HIF1α is recognized by the VHL gene product and is subjected to destruction. Therefore, SDHx mutations as well as VHL mutations lead to an increase in HIF1α-induced transcription, which is in part responsible for the neoplastic phenotype.
Mutations in several other genes, such as TMEM127 and MAX, have also recently been shown to predispose to the development of pheochromocytoma and paraganglioma.
Germline mutations in RET, VHL, SDHx, and others account for at least 20–30% of cases of isolated pheochromocytomas and paragangliomas. Given the high frequency of germline mutations, genetic counseling and genetic testing are recommended for all patients with pheochromocytomas or paragangliomas, particularly those with a positive family history, multifocal disease, or a diagnosis before age 50 years. Genetic testing may also be useful in screening families of carriers of mutations detected.
Almost all pheochromocytomas (about 90%) occur in the abdomen, and most of these (85%) are in the adrenal medulla. Extra-adrenal paragangliomas (including sympathetic and parasympathetic paragangliomas) are found in the perirenal area, the organ of Zuckerkandl, the urinary bladder, the heart, the neck, and the posterior mediastinum (Figure 12–1). Some of these tumors can lead to very specific symptoms (eg, urinary bladder pheochromocytoma can cause a hypertensive crisis with voiding). Grossly, pheochromocytomas are generally well-circumscribed but vary in size, with weights ranging from less than 1 g to several kilograms (Figure 12–3). They are highly vascular tumors and frequently have cystic, necrotic, or hemorrhagic areas. Microscopically, the tumor consists of large pleomorphic cells arranged in sheets separated by a highly vascular stroma. In the cytoplasm, there are catecholamine-containing storage granules similar to those in normal adrenal medullary cells. Mitoses are rare, but tumor invasion of the adrenal capsule and blood vessels is common even in benign pheochromocytomas. About 10% of pheochromocytomas are malignant. Malignancy is established only when a metastasis is found in a site where chromaffin cells are not usually demonstrated (eg, liver, lung, bone, or brain). Unfavorable prognostic factors suggesting a malignant course include large tumor size, local extension, younger age, DNA aneuploid tumors, dopamine secretion, and SDHB mutation.
Cross section of adrenal, showing a pheochromocytoma associated with hyperplasia of the medulla in a patient with multiple endocrine neoplasia type IIa. He also had a medullary carcinoma of the thyroid and a large pheochromocytoma in the opposite adrenal. (Reproduced, with permission, from Chandrasoma P et al, eds. Concise Pathology, 3rd ed. Originally published by Appleton & Lange. Copyright © 1998 by The McGraw-Hill Companies, Inc.)
Most pheochromocytomas release predominantly norepinephrine, but most also release epinephrine (Table 12–4). Rarely, a pheochromocytoma releases mostly or only epinephrine and very rarely mostly or only dopamine.
Table 12–4Pathophysiologic and clinical manifestations of catecholamine excess. ||Download (.pdf) Table 12–4 Pathophysiologic and clinical manifestations of catecholamine excess.
| || ||Catecholamine Excess |
|Target Tissue ||Physiologic Effect ||Pathophysiologic Manifestations ||Clinical Manifestations |
|Heart ||Increased heart rate ||Tachycardia ||Palpitations |
| || ||Tachyarrhythmia ||Angina pectoris |
| ||Increased contractility ||Increased myocardial O2 consumption ||Angina pectoris |
| || ||Myocarditis ||Heart failure |
| || ||Cardiomyopathy || |
|Blood vessels ||Arteriolar constriction ||Hypertension ||Headache |
| || || ||Heart failure |
| || || ||Angina pectoris |
| ||Venoconstriction ||Decreased plasma volume ||Dizziness |
| || || ||Orthostatic hypotension |
| || || ||Circulatory collapse |
|Gut ||Intestinal relaxation ||Impaired intestinal motility ||Ileus |
| || || ||Obstipation |
|Pancreas (B cells) ||Suppression of insulin release ||Carbohydrate intolerance ||Hyperglycemia |
| || || ||Glucosuria |
|Liver ||Increased glucose output ||Carbohydrate intolerance ||Hyperglycemia |
| || || ||Glucosuria |
|Adipose ||Lipolysis ||Increased free fatty acids ||Weight loss |
|Skin (apocrine glands) ||Stimulation ||Sweating ||Diaphoresis |
|Bladder neck ||Contraction ||Elevated urethral pressures ||Urinary retention |
|Most tissues ||Increased basal metabolic rate ||Increased heat production ||Heat intolerance |
| || || ||Sweating |
| || || ||Weight loss |
In about half of patients with pheochromocytoma, clinical manifestations vary in intensity and occur in an episodic or paroxysmal fashion. The paroxysms are related to sudden catecholamine discharge from the tumor. The sudden catecholamine excess causes hypertension, palpitations, tachycardia, chest pain, headache, anxiety, blanching, and excessive sweating. Such paroxysms usually occur several times a week but may occur only once every few months or up to 25 times daily. Paroxysms typically last for 15 minutes or less but may last for days. As time passes, the paroxysms usually become more frequent but generally do not change in character. A typical paroxysm may be produced by activities that compress the tumor (eg, bending, lifting, exercise, defecation, eating, or deep palpation of the abdomen) and by emotional distress or anxiety.
Other patients have persistently secreting tumors and more chronic symptoms, including sustained hypertension. However, such patients also usually experience paroxysms related to transient increases in catecholamine release. The long-term exposure to high levels of circulating catecholamines seems not to produce the classic hemodynamic responses observed after acute administration of catecholamines. This may be due in part to desensitization of the cardiovascular system to catecholamines and may explain why some patients with pheochromocytomas are entirely asymptomatic.
The clinical manifestations of pheochromocytoma are due to increased secretion of epinephrine and norepinephrine. Commonly reported manifestations are listed in Table 12–5.
Table 12–5Clinical findings in pheochromocytoma. ||Download (.pdf) Table 12–5 Clinical findings in pheochromocytoma.
|Symptoms ||Frequency (%) |
|Spells ||67 |
|Headache ||59 |
|Palpitations ||50 |
|Diaphoresis ||50 |
|Fainting episode ||40 |
|Bone pain ||35 |
|Weight loss ||30 |
|Anxiety ||19 |
|Nausea, vomiting ||19 |
|Dizziness ||18 |
|Flushing ||14 |
|Weakness, fatigue ||14 |
|Abdominal pain ||14 |
|Dyspnea ||13 |
|Paresthesias ||13 |
|Constipation ||11 |
|Chest pain ||12 |
|Flank pain ||7 |
|Visual symptoms ||7 |
|Diarrhea ||6 |
| Signs || |
|Hypertension ||92 |
| ||48 |
| ||44 |
|Fever ||28 |
|Tachycardia ||15 |
|Orthostatic hypotension ||12 |
|Palpable mass ||8 |
|Shock ||4 |
| Laboratory findings || |
|Hyperglycemia ||42 |
|Hypercalcemia ||4 |
|Polycythemia ||3 |
The classical pentad of symptoms in patients with pheochromocytoma consists of: headache, palpitation, perspiration, pallor, and orthostasis. The most common presenting feature of pheochromocytoma is hypertension. In about half of cases, hypertension is sustained but the blood pressure shows marked fluctuations, with peak pressures during symptomatic paroxysms. During a hypertensive episode, the systolic blood pressure can rise to as high as 300 mm Hg. In about one third of cases, hypertension is truly intermittent. In some individuals with pheochromocytoma, hypertension is absent. The blood pressure elevation caused by the catecholamine excess results from two mechanisms: α receptor–mediated vasoconstriction of arterioles, leading to an increase in peripheral resistance; and β1 receptor–mediated increases in cardiac output and in renin release, leading to increased circulating levels of angiotensin II. The increased total peripheral vascular resistance is probably primarily responsible for the maintenance of high arterial pressures.
Hypertensive crisis may be precipitated by a variety of drugs, including tricyclic antidepressants, antidopaminergic agents, metoclopramide, and naloxone. Beta blockers should not be administered until alpha blockade has been established. Otherwise, blockade of β2-adrenergic receptors, which promote vasodilation, will allow unopposed α-adrenergic receptor activation and produce marked vasoconstriction and hypertension.
Peripheral vasoconstriction, mediated by α receptors, causes both facial pallor and cool, moist hands and feet. Chronic vasoconstriction of the arterial and venous beds leads to a reduction in plasma volume and predisposes to postural hypotension. In others, orthostatic hypotension is associated with decreased cardiac stroke volume and an impaired response of total peripheral vascular resistance to changes in posture, perhaps indicative of diminished arteriolar and venous responsiveness. The reduced responsiveness of the vasculature to norepinephrine in patients with pheochromocytoma is probably related to downregulation of α-adrenergic receptors resulting from persistent elevations of norepinephrine levels.
Complications of pheochromocytoma are summarized in Table 12–6. If unrecognized and untreated, pheochromocytoma may be complicated by hypertensive retinopathy (retinal hemorrhages or papilledema); nephropathy; myocardial infarction, resulting from either myocarditis or coronary artery vasospasm; pulmonary edema, secondary either to left-sided heart failure or noncardiogenic causes; and stroke from cerebral infarction, intracranial hemorrhage, or embolism. Cerebral infarction results from hypercoagulability, vasospasm, or both. Hemorrhage occurs secondary to severe arterial hypertension. Emboli can originate in mural thrombi in patients with dilated cardiomyopathy. Cardiomyopathy during a catecholamine surge often resembles so-called takotsubo (stress/catecholamine-induced) cardiomyopathy (the so-called “broken heart” syndrome).
Table 12–6Complications of pheochromocytoma. ||Download (.pdf) Table 12–6 Complications of pheochromocytoma.
| Cardiovascular |
|ECG changes |
|Left ventricular hypertrophy |
|Subendocardial, intramyocardial hemorrhages |
|Acute myocardial infarction |
| Pulmonary |
| Gastrointestinal |
| Renal |
| Endocrine and metabolic |
| Skeletal |
| Skin |
| Crisis |
Obtundation, shock, disseminated intravascular coagulation, seizures, rhabdomyolysis, acute renal failure, death
In pregnancy, pheochromocytoma may lead to significant maternal morbidity and fetal demise.
The metabolic effects of excessive circulating catecholamines increase both blood glucose and free fatty acid levels. Increased glycolysis and glycogenolysis, combined with an α-adrenergic receptor–mediated inhibition of insulin release, cause the increase in blood sugar levels. In addition, epinephrine stimulates glucose production by gluconeogenesis and decreases insulin-mediated glucose uptake by peripheral tissues such as skeletal muscle. In pheochromocytoma, impaired glucose homeostasis may also result from β-adrenergic receptor desensitization, which produces relative insulin resistance. Glucose intolerance is common, and diabetes mellitus may occur.
Epinephrine raises blood lactate concentrations by stimulation of glycogenolysis and glycolysis. An increase in oxygen consumption from catecholamine stimulation of metabolism occurs in combination with a decrease in oxygen delivery to tissues from vasoconstriction, leading to lactate accumulation.
Occasionally, pheochromocytomas may also produce peptide hormones leading to specific paraneoplastic phenomena. For example, hypercalcemia may occur, related to excessive production of PTH-related peptide (PTHrP) in cases of malignant pheochromocytomas (as in some other malignancies) or to excessive production of PTH itself in cases of pheochromocytoma associated with MEN-2A–related hyperparathyroidism. Very rarely, ectopic production of adrenocorticotropic hormone (ACTH) by pheochromocytoma may lead to “ectopic” Cushing syndrome. Rare cases have been described in which a pheochromocytoma produces vasoactive intestinal peptide (VIP) (causing severe diarrhea), growth hormone–releasing hormone (GHRH) (causing acromegaly), corticotropin-releasing hormone (CRH) (Cushing syndrome), insulin (hypoglycemia), or other peptide hormones.
An increase in metabolic rate may cause weight loss (or, in children, lack of weight gain), and impaired heat loss from peripheral vasoconstriction may cause a mild elevation of basal body temperature, heat intolerance, flushing, or increased sweating.
During paroxysms, patients may experience marked anxiety, and when episodes are prolonged or severe, there may be visual disturbances, paresthesias, or seizures. A feeling of fatigue or exhaustion usually follows these episodes. Some patients present with psychosis or confusion.
There may be abdominal discomfort resulting from a large adrenal mass. Remarkably, some patients with pheochromocytomas are entirely asymptomatic.
Somewhat different clinical manifestations occur with predominantly epinephrine-releasing pheochromocytomas. Symptoms and signs include hypotension, prominent tachycardia, widened pulse pressure, cardiac arrhythmias, and noncardiogenic pulmonary edema. Acute hemorrhagic necrosis of the tumor may present initially as acute abdominal pain with marked hypertension, followed by hypotension, shock, and sudden death as a consequence of sudden cessation of catecholamine production (“fulminant pheochromocytoma crisis”). Death may also result from cardiovascular collapse secondary to prolonged vasoconstriction and loss of blood volume into the interstitium.
Patients with pure epinephrine-producing pheochromocytomas may be hypotensive because of epinephrine-induced peripheral vasodilation. Other patients with severe arterial vasoconstriction may appear to be in shock. In still others, the prolonged vasoconstriction of a hypertensive crisis may lead to shock.
Pheochromocytoma is diagnosed by demonstrating abnormally high concentrations of catecholamines or their breakdown products in the plasma or urine. Increases in plasma metanephrine and normetanephrine concentrations are greater and more consistent than increases in plasma catecholamines or urinary metanephrines. Pheochromocytoma tumor cells produce large amounts of metanephrines from catecholamines leaking from stores and metabolized by catechol-O-methyltransferase (COMT) present in pheochromocytoma cells. Thus, these metabolites are particularly useful for detecting pheochromocytomas. Thus, the elevated plasma levels of free metanephrine and normetanephrine in patients with pheochromocytoma are probably due mostly to metabolism before and not after release of the catecholamines into the circulation.
Plasma levels of chromogranin A (found in chromaffin granules) are significantly higher in patients with pheochromocytomas, especially those with malignant tumors. For malignant pheochromocytomas, serum chromogranin A levels can also be monitored during chemotherapy of malignant pheochromocytomas to gauge tumor response and to detect relapse.
Administration of the antihypertensive agent clonidine can be used to differentiate essential hypertension from hypertension caused by pheochromocytoma. This potent α2 agonist stimulates α2 receptors in the brain, reducing sympathetic outflow and blood pressure. A dose of 0.3 mg is given orally, and blood pressure and plasma catecholamine levels are determined periodically over the next 3 hours. Essential hypertension is partly dependent on centrally mediated catecholamine release. Administering clonidine normally suppresses sympathetic nervous system activity and substantially lowers plasma norepinephrine levels, reducing blood pressure. However, in patients with pheochromocytoma, the drug has little or no effect on plasma catecholamine levels because these tumors, which are not thought to be innervated, behave autonomously. Thus, the blood pressure remains unchanged.
Once a diagnosis of pheochromocytoma is made, the next step is to localize the neoplasm or neoplasms radiographically to permit surgical removal. Computed tomography (CT) or magnetic resonance imaging (MRI) can be used in tumor localization. CT and MRI have good sensitivity but poor specificity for detecting pheochromocytomas. Nuclear imaging studies such as iodine-131–metaiodobenzylguanidine scintigraphy have limited sensitivity but better specificity in diagnosis. For example, the specificity of 131I-metaiodobenzylguanidine scintigraphy is very good for confirming that a tumor is a pheochromocytoma and for ruling out metastatic disease. In addition, 6-[fluorine-18]-fluorodopamine positron emission tomography can aid in both diagnosis and localization of the tumor in patients with positive biochemical test results. Some pheochromocytomas also express somatostatin receptors and can be imaged with an OctreoScan, which uses radiolabeled somatostatin receptor agonists.
Surgery in patients with pheochromocytoma, including resection of the tumor itself, involves the risk of significant complications. Operative and postoperative complications are directly associated with preoperative systolic blood pressure, tumor size, excretion of urinary catecholamines and their metabolites, duration of anesthesia, and number of surgeries. Understanding the pathophysiology of pheochromocytoma is critically important in preparing the patient for surgery. For example, as noted previously, it is important that hypertension not be treated with β blockers, which could cause paradoxic worsening of hypertension by allowing unopposed α stimulation. Instead, an α receptor blocker, such as phenoxybenzamine, can be used effectively.
What genetic mutations are found in patients with pheochromocytoma?
What are the symptoms and signs of pheochromocytoma?
What are some complications of untreated pheochromocytoma?
What are the metabolic and neurologic effects of pheochromocytoma?
How is the diagnosis of pheochromocytoma made?