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, less commonly, episodichypertension. Pheochromocytomas that
secrete epinephrine cause hypertension less often; more frequently,
they produce episodic hyperglycemia, glucosuria, and other metabolic
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 12–2 Clinical Features of Pheochromocytoma. |Favorite Table|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 less commonly episodichypertension, sweating,
palpitations, hyperglycemia, glycosuria|
|Occasionally asymptomatic (found incidentally on CT scan
|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 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
(occurring mainly in the head and neck area). 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 (Recklinghausen’s
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
Table 12–3 Major Genetic Syndromes Associated with Pheochromocytoma. |Favorite Table|Download (.pdf)
Table 12–3 Major Genetic Syndromes Associated with Pheochromocytoma.
|MEN-2a||Medullary thyroid carcinoma||50% develop pheochromocytoma||RET||10q11.2|
|Parathyroid hyperplasia||Bilateral, asynchronous pheochromocytoma|
|MEN-2b||Medullary thyroid carcinoma|
|NFI||Neurofibromas||0.1–5.0% develop pheochromocytoma
(20–50% of hypertensive patients)||NFI||17q11.2|
|Lisch nodules||90% benign |
|Sphenoid dysplasia||10% bilateral|
|Axillary and inguinal freckling||6% extra-adrenal|
|VHL||Hemangioblastomas (brain, spine, retina)||20% develop pheochromocytoma||VHL||3p26-25|
|Clear-cell renal cell cancer|
|PGL1-4||Paraganglioma (parasympathetic or sympathetic)||30% of SDHB pheochromocytoma
In MEN-2a syndrome (Sipple’s 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 40% of patients with MEN-2a
and MEN-2b have bilateral pheochromocytomas. The gene responsible
for MEN-2a and MEN-2b has now been localized to chromosome 10q11.2.
In 1993, more than two dozen different families with MEN-2a were
found to have missense point mutations of the RET proto-oncogene,
a tyrosine kinase receptor gene expressed at low levels in normal
human thyroid tissue and at high levels in medullary thyroid carcinoma
and pheochromocytoma tissue. Subsequently, it was documented that
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 pheochromocytoma
as part of MEN-2a and mutations at a different position (codon 918),
with pheochromocytoma as part of MEN-2b. These germline mutations
of the RET proto-oncogene were the first examples
of a dominantly acting oncogenic point mutation causing a heritable
neoplasm in humans. These missense mutations can be detected by
DNA analysis, allowing identification of MEN carriers.
More recently, it has been determined that other familial cases
of pheochromocytoma, also transmitted in autosomal dominant fashion,
are caused by germline mutations in genes coding for subcomponents
of the succinate-dehydrogenase complex (SDHD, SDHB, SDHC).
Germline mutations in RET, VHL, SDHB, SDHC, and SDHD taken
together account for more than 20% of cases of isolated
pheochromocytomas. Among all patients with pheochromocytoma, including
those with known hereditary syndrome or a positive family history,
the frequency of germline mutations in these four genes together
approaches 30%. Given the high frequency of germline mutations,
some experts now recommend genetic evaluation, genetic counseling,
and perhaps genetic testing for all patients with pheochromocytomas,
particularly those with a positive family history, multifocal disease,
or a diagnosis before age 50 years. However, this age cutoff may
not capture all hereditary cases; for example, the mean age at the
diagnosis in SDHD pheochromocytomas is 43 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
pheochromocytomas (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). Extra-adrenal pheochromocytomas account
for 10% of all pheochromocytomas in adults and 30–40% of
pheochromocytomas in children. They are usually larger than adrenal
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, 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, Taylor CE. 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 12–4 Pathophysiologic and Clinical Manifestations of Catecholamine Excess. |Favorite Table|Download (.pdf)
Table 12–4 Pathophysiologic and Clinical Manifestations of Catecholamine Excess.
|Target Tissue||Physiologic Effect||Catecholamine
|Pathophysiologic Manifestations||Clinical Manifestations|
|Heart||Increased heart rate||Tachycardia||Palpitations|
|Increased contractility||Increased myocardial O2 consumption||Angina pectoris|
|Myocarditis||Congestive heart failure|
|Blood vessels||Arteriolar constriction||Hypertension||Headache|
|Congestive heart failure|
|Venoconstriction||Decreased plasma volume||Dizziness|
|Gut||Intestinal relaxation||Impaired intestinal motility||Ileus|
|Pancreas (B cells)||Suppression of insulin release||Carbohydrate intolerance||Hyperglycemia|
|Liver||Increased glucose output||Carbohydrate intolerance||Hyperglycemia|
|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|
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 12–5 Clinical Findings in Pheochromocytoma. |Favorite Table|Download (.pdf)
Table 12–5 Clinical Findings in Pheochromocytoma.
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
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 congestive 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.
Table 12–6 Complications of Pheochromocytoma. |Favorite Table|Download (.pdf)
Table 12–6 Complications of Pheochromocytoma.
|Arrhythmias||Renal artery stenosis (resulting from kinking
by adrenal mass)|
|Ventricular tachycardia||Renal infarction|
|Torsades de pointes||Endocrine and metabolic|
|Wolff-Parkinson-White syndrome||Hyperglycemia, glucose intolerance, diabetic
|ECG changes||Thyrotoxicosis (transient)|
|ST segment elevations or depressions||Reactivation of Graves’ disease|
|Inverted or flattened T waves||Hypercalcemia|
|Prolonged QT intervals||Lactic acidosis|
|High or peaked P waves||Fever|
|Dilated||Osseous microthrombi (from hemoconcentration)|
|Left ventricular hypertrophy||Skin|
|Subendocardial, intramyocardial hemorrhages||Crisis|
|Acute myocardial infarction||Obtundation, shock, disseminated
intravascular coagulation, seizures, rhabdomyolysis, acute renal
|Pulmonary edema (noncardiogenic)|
|Acute abdominal pain|
Ileus and obstipation are typical. However, diarrhea may occur
as a result of rare adrenal production of vasoactive intestinal
peptide (VIP) or dopamine.
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.
Occasionally, ectopic production of adrenocorticotropic hormone
(ACTH) by pheochromocytoma may lead to “ectopic” Cushing’s
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’s 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
There may be abdominal discomfort resulting from a large adrenal
mass. Remarkably, some patients with pheochromocytomas are entirely
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 concentrations
are greater and more consistent than increases in plasma catecholamines
or urinary metanephrines. This is perhaps because metanephrines
persist in plasma longer than catecholamines and exhibit less variability in
response to changes in posture. A reliable assay showing increased
plasma or urine levels of metanephrines is usually sufficient to
establish the diagnosis. If the patient has paroxysmal symptoms,
sampling of blood or timed urine collections during an episode may
be needed to establish the diagnosis. Studies have shown significant
positive correlations between excretion of catecholamine metabolites
and tumor volume.
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 meta-nephrines 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 malignant pheochromocytomas
than in those with benign tumors. Thus, markedly elevated chromogranin
A levels may point to the diagnosis of a malignant pheochromocytoma.
Serum chromogranin A levels can also be monitored during chemotherapy
of malignant pheochromocytomas to gauge tumor response and to detect
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 or indium-111–DTPA-D-Phe-pentetreotide scanning 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
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 beta-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.
- 7. What genetic mutations are
found in patients with pheochromocytoma?
- 8. What are the symptoms and signs
- 9. What are some complications of
- 10. What are the metabolic and neurologic
effects of pheochromocytoma?
- 11. How is the diagnosis of pheochromocytoma