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Clinical presentation and diagnosis of

pheochromocytoma
AUTHOR: William F Young, Jr, MD, MSc
SECTION EDITOR: Lynnette K Nieman, MD
DEPUTY EDITOR: Katya Rubinow, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jun 2024.

This topic last updated: Jun 11, 2024.

INTRODUCTION

Catecholamine-secreting tumors that arise from chromaffin cells of the adrenal medulla and the
sympathetic ganglia are referred to as "pheochromocytomas" and "catecholamine-secreting
paragangliomas" ("extra-adrenal pheochromocytomas"), respectively. Because the tumors have
similar clinical presentations and are treated with similar approaches, many clinicians use the
term "pheochromocytoma" to refer to both adrenal pheochromocytomas and catecholamine-
secreting paragangliomas. However, the distinction between pheochromocytoma and
paraganglioma is an important one because of implications for associated neoplasms, risk for
malignancy, and genetic testing.

The clinical presentation and approach to diagnosis of pheochromocytoma are reviewed here.
The genetics and treatment of pheochromocytoma and the clinical manifestations, diagnosis,
and treatment of paragangliomas are discussed separately. (See "Pheochromocytoma in
genetic disorders" and "Treatment of pheochromocytoma in adults" and "Paragangliomas:
Epidemiology, clinical presentation, diagnosis, and histology".)

EPIDEMIOLOGY

Catecholamine-secreting tumors are rare neoplasms, probably occurring in less than 0.2
percent of patients with hypertension [1,2]. It is estimated that the annual incidence of
pheochromocytoma is approximately 0.8 per 100,000 person-years [3]. However, this is likely to
be an underestimate as 50 percent of pheochromocytomas were diagnosed at autopsy in one
series [4]. Although pheochromocytomas may occur at any age, they are most common in the
fourth to fifth decade and are equally common in males and females [5]. Tumor characteristics
are described below. (See 'Tumor characteristics' below.)

Most catecholamine-secreting tumors are sporadic. However, approximately 40 percent of

patients have the disease as part of a familial disorder; in these patients, the catecholamine-
secreting tumors are more likely to be bilateral adrenal pheochromocytomas or
paragangliomas.

Hereditary catecholamine-secreting tumors typically present at a younger age than sporadic

neoplasms [6]. Sporadic pheochromocytoma is usually diagnosed on the basis of symptoms or
an incidental discovery on computed imaging, whereas syndromic pheochromocytoma is
frequently diagnosed earlier in the course of disease because of biochemical surveillance or
genetic testing. (See "Pheochromocytoma in genetic disorders".)

There are several familial disorders associated with adrenal pheochromocytoma, all of which
have autosomal dominant inheritance: von Hippel-Lindau (VHL) syndrome, multiple endocrine
neoplasia type 2 (MEN2), and less commonly, neurofibromatosis type 1 (NF1). The approximate
frequency of pheochromocytoma in these disorders is 10 to 20 percent in VHL syndrome, 50
percent in MEN2, and 2 to 3 percent with NF1. (See "Pheochromocytoma in genetic disorders".)

CLINICAL PRESENTATION

Pheochromocytoma is usually suggested by the history in a symptomatic patient, discovery of a

lipid-poor incidental adrenal mass, or the family history in a patient with familial disease. In one
report of 107 patients, the average age at diagnosis was 47 years, and the average tumor size
was 4.9 cm [5].

Symptoms and signs — Symptoms are present in approximately 50 percent of patients with
pheochromocytoma, and when present, they are typically paroxysmal.

Classic triad — The classic triad of symptoms in patients with a pheochromocytoma consists
of episodic headache, sweating, and tachycardia [1,7]. Approximately one-half have paroxysmal
hypertension; most of the rest have either primary hypertension (formerly called "essential"
hypertension) or normal blood pressure. Most patients with pheochromocytoma do not have
the three classic symptoms [8,9], and patients with primary hypertension may have paroxysmal
symptoms [10].
 ● Sustained or paroxysmal hypertension is the most common sign of pheochromocytoma,
but approximately 5 to 15 percent of patients present with normal blood pressure. The
frequency of normotension is higher in patients with adrenal incidentaloma or in those
undergoing periodic screening for familial pheochromocytoma [7,11,12].

● Headache, which may be mild or severe and variable in duration, occurs in up to 90

percent of symptomatic patients [12].

● Generalized sweating occurs in up to 60 to 70 percent of symptomatic patients. Other

symptoms include forceful palpitations, tremor, pallor, dyspnea, generalized weakness,
and panic attack-type symptoms (particularly in pheochromocytomas that produce
epinephrine) [13].

● On rare occasions, patients present with a condition termed pheochromocytoma crisis, or

pheochromocytoma multisystem crisis. These individuals may have either hypertension or
hypotension, hyperthermia (temperature >40°C), mental status changes, and other organ
dysfunction [14].

Less common symptoms and signs

● Orthostatic hypotension and others – Other signs and symptoms that may occur
include orthostatic hypotension (which may reflect a low plasma volume), visual blurring,
papilledema, weight loss, polyuria, polydipsia, constipation, increased erythrocyte
sedimentation rate, insulin resistance, hyperglycemia, leukocytosis, psychiatric disorders,
and, rarely, secondary erythrocytosis due to overproduction of erythropoietin [7,15]. (See
"Diagnostic approach to the patient with erythrocytosis/polycythemia", section on
'Secondary polycythemia'.)

● Cardiomyopathy – Rarely, pheochromocytoma is associated with cardiomyopathy

attributed to catecholamine excess that is similar to stress-induced (takotsubo)
cardiomyopathy [16]. Patients may present with pulmonary edema and may deteriorate
with initiation of beta-adrenergic blockade [17]. Global or focal wall motion abnormalities
may improve with surgical or medical treatment of the pheochromocytoma. (See "Clinical
manifestations and diagnosis of stress (takotsubo) cardiomyopathy".)

● Paroxysmal elevations in blood pressure – Patients with symptoms related to

paroxysmal elevations in blood pressure (hypertension, tachycardia, or arrhythmia) during
diagnostic procedures (eg, colonoscopy), induction of anesthesia, surgery, with certain
foods or beverages containing tyramine, or with certain drugs (such as beta-adrenergic
 blockers, tricyclic antidepressants, corticosteroids, metoclopramide or monoamine
oxidase inhibitors [MAOIs]) should undergo formal evaluation for pheochromocytoma.

The abnormalities in carbohydrate metabolism that occur (insulin resistance, impaired fasting
glucose, apparent type 2 diabetes mellitus) are directly related to the increase in catecholamine
production [18]. These changes resolve after removal of the catecholamine-secreting neoplasm
[19].

The symptoms of pheochromocytomas are caused by tumoral hypersecretion of one or

combinations of the following catecholamines: norepinephrine, epinephrine, and dopamine;
increased central sympathetic activity may also contribute [7]. There are two rare presentations
of pheochromocytoma: patients with tumors that secrete only epinephrine can present with
episodic hypotension [20,21], and rapid cyclic fluctuations (eg, every 7 to 15 minutes) of
hypertension and hypotension can occur via an uncertain mechanism [22,23]. Fluid repletion
and treatment with an alpha-adrenergic antagonist may be beneficial in the latter patients.

Asymptomatic patients — With the more widespread use of computed imaging and genetic
testing, an increasing number of pheochromocytoma patients are diagnosed in the
presymptomatic stage; eg, during the evaluation of an adrenal incidentaloma or on germline
pathogenic variant-based case detection. In approximately 60 percent of patients, the tumor is
discovered incidentally during computed tomography (CT) or magnetic resonance imaging
(MRI) of the abdomen for unrelated symptoms [8,9,24-26]. (See "Evaluation and management of
the adrenal incidentaloma".)

In a study of 296 consecutive patients with pheochromocytoma treated from 2005 to 2016, 61
percent (180 of 296) were discovered as an incidental finding on cross-section imaging (see
'Imaging' below), 27 percent (80 of 296) due to pheochromocytoma-related symptoms, and 12
percent (36 of 296) on genetic variant-based testing [26]. The germline pathogenic variant-
based pheochromocytomas were smaller and required less alpha-adrenergic blockade
preoperatively (median cumulative phenoxybenzamine dose 270 versus 375 versus 450 mg for
germline pathogenic variant-based, incidental-finding, and symptomatic groups, respectively).
In many patients, pheochromocytoma is found only at autopsy [4,27].

Patients with familial pheochromocytoma — When pheochromocytoma is associated with

the multiple endocrine neoplasia type 2 (MEN2), symptoms are present in only approximately
one-half of patients, and only one-third have hypertension [28]. It is not known whether this
difference is due to screening for pheochromocytoma in patients with MEN2 or a real difference
in the clinical expression of the disease. A similar finding has been observed with
pheochromocytoma associated with von Hippel-Lindau (VHL) disease as 35 percent of patients
have no symptoms, a normal blood pressure, and normal laboratory values for fractionated
catecholamines and metanephrines [29]. (See "Pheochromocytoma in genetic disorders".)

Tumor characteristics

Location — Approximately 95 percent of catecholamine-secreting tumors are in the abdomen,

85 to 90 percent of which are intraadrenal (pheochromocytoma), and 5 to 10 percent are
multiple [7,30]. Approximately 10 to 15 percent of catecholamine-secreting tumors are extra-
adrenal and are referred to as catecholamine-secreting paragangliomas. (See "Paragangliomas:
Epidemiology, clinical presentation, diagnosis, and histology".)

Malignant potential — Approximately 10 percent of all catecholamine-secreting tumors are

metastatic (frequency ranges from 8.3 to 13 percent) [7,31-33]. Malignant pheochromocytomas
are histologically and biochemically the same as benign ones. The only reliable clue to the
presence of a malignant pheochromocytoma is local invasion into surrounding tissues and
organs (eg, kidney, liver) or distant metastases, which may occur as long as 53 years after
resection [32-34]. Thus, even when pheochromocytomas or paragangliomas are considered
"benign" on pathologic examination, long-term follow-up is indicated in all patients to confirm
that impression. Patients with the succinate dehydrogenase (SDH) subunit B pathogenic
variants are more likely to develop metastatic disease [11,35,36].

A variety of immunohistochemical and other prognostic markers have been evaluated for
association with malignancy in adrenal pheochromocytomas [37,38], with mixed results to date.
According to the 2017 World Health Organization (WHO), all pheochromocytomas have some
metastatic potential [38]. This is also true for paragangliomas. (See "Paragangliomas:
Epidemiology, clinical presentation, diagnosis, and histology", section on 'Histology and
malignant potential'.)

APPROACH TO INITIAL EVALUATION

The diagnosis of pheochromocytoma is made based upon biochemical confirmation of

catecholamine hypersecretion, followed by identifying the tumor with imaging studies.
However, biochemical tests can be normal in an asymptomatic patient with a small (eg, <2 cm)
and lipid-poor adrenal incidentaloma as these may be discovered in their "prebiochemical"
phase. In these cases, the imaging phenotype guides management (see 'Imaging' below). Of
note, even among patients suspected to have a pheochromocytoma, the diagnosis is rarely
confirmed. In one series, as an example, the diagnosis was established in only 1 of 300 patients
evaluated for pheochromocytoma [39].
Indications for testing — Pheochromocytoma should be suspected in patients who have one
or more of the following:

● The classic triad of headache, sweating, and tachycardia, whether or not they have
hypertension.

● Hyperadrenergic spells (eg, self-limited episodes of nonexertional palpitations,

diaphoresis, headache, tremor, or pallor). However, most patients with spells do not have
pheochromocytoma.

● Onset of hypertension at a young age (eg, <20 years), resistant hypertension, or

hypertension with new-onset or atypical diabetes mellitus (eg, new onset of apparent type
2 diabetes in a person without risk factors).

● A familial syndrome that predisposes to catecholamine-secreting tumors (eg, multiple

endocrine neoplasia type 2 [MEN2], neurofibromatosis type 1 [NF1], or von Hippel-Lindau
[VHL]).

● A family history of pheochromocytoma.

● Lipid-poor (unenhanced CT attenuation >10 HU) adrenal incidentaloma with or without

hypertension.

● Pressor response during anesthesia, surgery, or angiography.

● Idiopathic dilated cardiomyopathy.

● A history of gastric stromal tumor or pulmonary chondromas (Carney triad).

Discontinue interfering medications — Although it is preferred that patients not receive any
medication during the diagnostic evaluation, treatment with all antihypertensive medications
may be continued. Tricyclic antidepressants interfere most frequently with the interpretation of
plasma fractionated metanephrines and 24-hour urinary catecholamines and metabolites. To
effectively screen for catecholamine-secreting tumors, treatment with tricyclic antidepressants
(including the muscle relaxant cyclobenzaprine) and other psychoactive agents (but not
selective serotonin reuptake inhibitors [SSRIs]) listed in the table ( table 1) should be tapered
and discontinued at least two weeks before any hormonal assessments.

There are certainly clinical situations for which it is contraindicated to discontinue certain
medications (eg, antipsychotics), and if biochemical testing is positive, then computed imaging
(eg, CT scan of the abdomen and pelvis) would be needed to exclude a catecholamine-secreting
tumor. Furthermore, catecholamine secretion may be appropriately increased in situations of
physical stress or illness (eg, any significant illness requiring hospitalization, stroke, myocardial
infarction, congestive heart failure, obstructive sleep apnea) [40]. Therefore, the clinical
circumstances under which catecholamines and metanephrines are measured must be
assessed in each case.

Levodopa is the most common and only pharmacotherapeutic agent that causes markedly
abnormal levels of dopamine.

Initial biochemical tests — The diagnosis of pheochromocytoma is typically made by

measurements of urinary and plasma fractionated metanephrines and catecholamines
( algorithm 1). However, there are major regional, institutional, and international differences
in the approach to the biochemical diagnosis of pheochromocytoma [2,41-43].

We suggest initial biochemical testing based upon the index of suspicion that the patient has a
pheochromocytoma. If there is a low index of suspicion, we suggest 24-hour urinary
fractionated catecholamines and metanephrines; if there is a high index of suspicion, we
suggest plasma fractionated metanephrines. Our approach differs from the 2014 Endocrine
Society clinical practice guideline, which suggests initial biochemical testing using 24-hour
urinary fractionated metanephrines or plasma fractionated metanephrines (drawn supine with
an indwelling cannula for 30 minutes) [44]. However, many clinicians do not measure plasma
fractionated metanephrines under these ideal conditions, and the test is associated with a high
false-positive rate [44,45].

The majority of the metabolism of catecholamines is intratumoral, with formation of

metanephrine and normetanephrine [46]. Most laboratories now measure fractionated
catecholamines (dopamine, norepinephrine, and epinephrine) and fractionated metanephrines
(metanephrine and normetanephrine) by high-performance liquid chromatography (HPLC) with
electrochemical detection or tandem mass spectroscopy (MS/MS) [47]. These techniques have
overcome the problems with fluorometric analysis (eg, false-positive results caused by alpha-
methyldopa, labetalol, or sotalol, and false-negative results caused by imaging contrast agents).

The protocols for the collection and storage of the 24-hour urine collection are determined by
the laboratory where the assay will be performed. For example, some laboratories standardized
their assays on urine that was kept refrigerated during the collection, while some laboratories
(eg, Mayo Medical Laboratories) standardized their assays for urine kept at room temperature.

For any of the biochemical tests, sensitivity will be lower and specificity will be higher for
hereditary compared with sporadic pheochromocytoma because tumors detected in patients
with a familial disposition tend to be small tumors that release catecholamines in amounts that
are often too low to be detected. In contrast, sporadic pheochromocytomas tend to be larger
and present with typical signs and symptoms of catecholamine excess. Our suggested approach
to testing based upon the patient's clinical presentation is discussed here.

Measurement of plasma fractionated metanephrines is useful to rule out pheochromocytoma,

but a positive test (ie, plasma normetanephrine above the upper limit of the reference range)
only slightly increases suspicion of disease when screening for sporadic pheochromocytoma.

Low risk for pheochromocytoma — 24-hour urinary fractionated catecholamines and

metanephrines should be the first test in patients with a somewhat lower index of suspicion for
pheochromocytoma. This includes patients with:

● Resistant hypertension

● Hyperadrenergic spells (eg, self-limited episodes of nonexertional palpitations,

diaphoresis, headache, tremor, or pallor)

24-hour urine fractionated metanephrines and catecholamines — At Mayo Clinic, the

most reliable case-detection method for identifying catecholamine-secreting tumors is
measuring fractionated metanephrines and catecholamines in a 24-hour urine collection
(sensitivity = 98 percent, specificity = 98 percent) [41,48,49].

The 24-hour urine collection for fractionated metanephrines and catecholamines should include
measurement of urinary creatinine to verify an adequate collection. The diagnostic cutoffs for
most 24-hour urinary fractionated metanephrine assays are based on normal ranges derived
from a normotensive volunteer reference group, and this can result in a high rate of false-
positive results. As an example, in normotensive laboratory volunteers, the 95th percentiles are
428 mcg for normetanephrine and 200 mcg for metanephrine; whereas the 95th percentiles in
individuals being tested for pheochromocytoma (but who do not have the neoplasm) as part of
routine clinical practice are 71 and 51 percent higher than those of normal volunteers,
respectively [49].

High risk for pheochromocytoma — The index of suspicion for a catecholamine-secreting

tumor should be high for the following scenarios:

● A family history of pheochromocytoma.

● A genetic syndrome that predisposes to pheochromocytoma (eg, MEN2).

● A past history of resected pheochromocytoma.

 ● An incidentally discovered adrenal mass that has imaging characteristics consistent with
pheochromocytoma (eg, unenhanced CT attenuation [measured in Hounsfield units (HU)]
>10 HU and marked enhancement with intravenous [IV] contrast medium on CT or high
signal intensity on T2-weighted MRI, and or cystic and hemorrhagic changes seen on CT or
MRI) [50].

Measuring plasma fractionated metanephrines is a first-line test when there is a high index of
suspicion for pheochromocytoma. Plasma fractionated metanephrines are also a good first-line
test for children because obtaining a complete 24-hour urine collection is difficult. (See "Patient
education: Collection of a 24-hour urine specimen (Beyond the Basics)".)

Plasma fractionated metanephrines — Some groups have advocated that plasma

fractionated metanephrines should be a first-line test for pheochromocytoma [42,51]; the
predictive value of a negative test is extremely high, and normal plasma fractionated
metanephrines exclude pheochromocytoma except in patients with early preclinical disease and
those with strictly dopamine-secreting neoplasms [41]. A plasma test is also attractive because
of simplicity.

Although measurement of plasma fractionated metanephrines has a sensitivity of 96 to 100

percent [41,42], the specificity is poor at 85 to 89 percent [41,42,52]; the specificity falls to 77
percent in patients older than 60 years [41]. It has been estimated that 97 percent of patients
with hypertension seen in a tertiary care clinic who have positive plasma fractionated
metanephrine measurements will not have a pheochromocytoma [52].

This high rate of false-positive tests results in excessive health care expenditures because of
subsequent imaging and potentially inappropriate surgery [52]. Thus, plasma fractionated free
metanephrines lack the necessary specificity to be recommended as a first-line test; therefore,
this measurement is reserved for cases for which the index of suspicion is high ( algorithm 1).

Measurement of urinary or plasma dopamine and 3-methoxytyramine may be very useful in

detecting the rare tumor with selective dopamine hypersecretion because plasma
metanephrine fractions are not direct metabolites of dopamine and may be normal in the
setting of a dopamine-secreting tumor [41,53].

Normal results — If results are normal, no further evaluation is necessary, except for patients
being evaluated for spells. Testing should be repeated during a spell: patients are instructed to
start the 24-hour urine collection when they have a typical spell by recalling back to when they
last urinated before the spell and collect to that time point the next day. If results are still
normal on repeat testing, other causes of spells should be investigated.
 Positive case-detection test — A positive test for a catecholamine-secreting tumor includes
one or more of the following findings:

● 24-hour urine fractionated metanephrines, catecholamines, and 3-methoxytyramine:

• Normetanephrine >900 mcg/24 hours or metanephrine >400 mcg/24 hours

( algorithm 1)
• Norepinephrine >170 mcg/24 hours
• Epinephrine >35 mcg/24 hours
• Dopamine >700 mcg/24 hours
• 3-methoxytyramine >306 mcg/24 hours in males and >242 mcg/24 hours in females

● Plasma fractionated metanephrines:

• The normal ranges for plasma metanephrine and normetanephrine depend upon the
method used to obtain the blood sample:

For an indwelling cannula, for 20 minutes following an overnight fast before the blood
draw, the diagnostic cutoffs to exclude pheochromocytoma are metanephrine <0.3
nmol/L and/or normetanephrine <0.66 nmol/L [54].

For venipuncture in a seated, ambulant, nonfasting patient, the diagnostic cutoffs to

exclude pheochromocytoma are slightly higher: metanephrine <0.5 nmol/L and/or
normetanephrine <0.9 nmol/L [34].

For patients with biochemical confirmation of the diagnosis, the next step is radiologic
evaluation to locate the tumor. (See 'Imaging' below.)

Indeterminate case-detection test — For patients with indeterminate test results (ie, above
the upper limit of the reference interval for the laboratory but below the threshold for positive
case detection), additional testing is based upon the clinical index of suspicion that the patient
has a pheochromocytoma.

● For patients with high index of suspicion (family history, incidentally discovered adrenal
mass with imaging characteristics consistent with pheochromocytoma), obtain (or repeat)
plasma fractionated metanephrines. If the initial sample was a seated plasma fractionated
metanephrines, it is reasonable to obtain a supine sample [45].

● For patients with low index of suspicion (eg, resistant hypertension, self-limited episodes
of nonexertional palpitations, diaphoresis, headache, tremor, or pallor), obtain (or repeat)
24-hour urinary fractionated catecholamines, metanephrines, and creatinine.
Approaches for specific patient groups

● Spells – Patients with spells (defined as a sudden onset of a symptom or symptoms that
are recurrent, self-limited, and stereotypic in nature) that relate to paroxysmal elevations
in blood pressure should be evaluated for pheochromocytoma [10]. However, the clinician
should recognize that most patients with spells do not have a pheochromocytoma [10].

We suggest initial screening with 24-hour urinary fractionated metanephrines in this

setting because we do not consider these patients to be at high risk for
pheochromocytoma. The 24-hour urinary fractionated metanephrines are similar in
sensitivity to plasma fractionated metanephrines but higher in specificity, in our
experience ( algorithm 1) [41,48]. If initial results are normal, testing should be repeated
during a spell. (See 'Normal results' above.)

Other possible causes of "spells" that may be confused with pheochromocytoma include
hyperthyroidism, menopausal symptoms, idiopathic flushing disorder (eg, unexplained
flushing spells), carbohydrate intolerance, hyperadrenergic spells, labile primary
hypertension (formerly called "essential" hypertension), renovascular disease,
hypoglycemia, postural orthostatic tachycardia syndrome (POTS), mast cell disease, and
carcinoid syndrome ( table 2).

Additional evaluation for other causes, in particular endocrine causes such as carcinoid
syndrome, should be based upon patient presentation. As an example, a patient who
presents with flushing and diarrhea rather than pallor with associated
pheochromocytoma-like symptoms should undergo 24-hour urinary excretion of 5-
hydroxyindoleacetic acid (HIAA). However, we do not suggest testing this in all patients
who are being evaluated for possible pheochromocytoma.

● Adrenal incidentalomas – If the noncontrast CT attenuation is less than 10 HU,

biochemical testing for pheochromocytoma is not needed [55]. In a series of 158 adrenal
pheochromocytomas measuring more than 4 cm in diameter, the median noncontrast
radiodensity was 33 HU (range 18 to 60 HU)] [55]. In a multicenter, retrospective study of
533 patients with 548 histologically confirmed pheochromocytomas, unenhanced CT
attenuation data were available in 376, of which 374 pheochromocytomas had an
unenhanced CT attenuation of >10 HU (99.5 percent). In the two exceptions (0.5 percent),
the unenhanced CT attenuation was exactly 10 HU [56].

We suggest measuring 24-hour urinary fractionated metanephrines and catecholamines

routinely in patients with adrenal incidentalomas when the CT attenuation is 10 HU or
greater ( algorithm 1) [57]. Approximately 3 percent of adrenal incidentalomas prove to
 be pheochromocytomas [58]. We suggest that plasma fractionated metanephrines also be
measured if the lipid-poor adrenal mass is vascular in concert with other features (eg,
cystic and hemorrhagic changes) to suggest pheochromocytoma [50,58]. Plasma
fractionated metanephrines are very sensitive (97 to 100 percent) but not very specific (85
to 89 percent) for pheochromocytoma.

If the biochemical tests in patients with adrenal masses more than 2 cm in diameter are
negative, a functioning adrenal pheochromocytoma is excluded. However, small adrenal
pheochromocytomas (<2 cm in diameter) may not be biochemically detectable [26].
Adrenal incidentalomas should be followed with both imaging and repeat biochemical
testing. The evaluation of adrenal incidentalomas is reviewed in detail separately. (See
"Evaluation and management of the adrenal incidentaloma".)

● Paroxysmal hypertension – Patients with hypertension that is paroxysmal or poorly

responsive to standard therapy should be evaluated. The pretest probability of a
pheochromocytoma in this scenario is low. We would therefore suggest testing with 24-
hour urinary fractionated metanephrines ( algorithm 1). If the results are normal, no
further testing is needed, while if the results are significantly elevated, imaging with CT or
MRI is indicated. The biochemical criteria for a positive test depend on the reference
laboratory that is used. As an example, if the 24-hour urinary fractionated metanephrines
are tested at Mayo Medical Laboratories, the diagnostic cutoffs are >400 mcg for
metanephrines, >900 mcg for normetanephrines, and >1000 mcg for total metanephrines
( algorithm 1).

Paroxysmal hypertension is a classic sign of pheochromocytoma, but patients with this

finding rarely have the disorder. Its presence commonly initiates an aggressive evaluation
to uncover a pheochromocytoma; after a pheochromocytoma has been excluded, the
condition usually remains undiagnosed, thereby resulting in ineffective therapy. This
disorder, named pseudopheochromocytoma or hyperadrenergic spells, may be due to
stress or emotional distress that is only uncovered after careful psychological evaluation
[59]. (See "Paroxysmal hypertension (pseudopheochromocytoma)".)

● Increased sympathetic activity – Sympathetic activity is also increased in several

conditions other than pheochromocytoma. As an example, abrupt discontinuation of a
short-acting sympathetic antagonist drug (such as clonidine or propranolol) can lead to
severe hypertension and coronary ischemia, probably due to upregulation of sympathetic
receptors during the period of sympathetic blockade. When this obvious cause and effect
relationship is evident, testing for pheochromocytoma is not needed. (See "Tapering and
discontinuing antihypertensive medications".)
 Increased sympathetic activity potentially leading to severe hypertension can also occur in
patients with several other disorders. These include [60]:

• Autonomic dysfunction, as in the Guillain-Barré syndrome or post-spinal cord injury.

• A stress response after cardiac bypass surgery or during a panic reaction [61].
Hypertension in the latter patients occurs primarily during treatment with a tricyclic
antidepressant drug, which may increase the degree of sympathetic arousal.

• Pheochromocytoma is often considered in patients with undiagnosed panic disorder, in

whom many of the symptoms are due to increased sympathetic activity (see "Panic
disorder in adults: Treatment overview"). In one study, 40 percent of patients evaluated
for pheochromocytoma met the criteria for panic disorder, as compared with 5 percent
of control patients with hypertension [61].

• The use of sympathomimetic drugs, such as cocaine, amphetamines, phencyclidine,

epinephrine, phenylephrine, terbutaline, or the combination of a monoamine oxidase
inhibitor (MAOI) and the ingestion of tyramine-containing foods [62-66]. Tyramine,
which is produced from the bacterial breakdown of tyrosine, is normally inactivated by
monoamine oxidase in the intestinal tract. This inactivation does not occur in the
presence of an MAOI, leading to the absorption of tyramine, which increases the
release of norepinephrine from nerve endings and epinephrine from the adrenal gland.
The ensuing hypertensive reaction is dose dependent and can be exacerbated if the
patient is also taking a sympathomimetic drug.

The three major MAOIs available in the United States are the antidepressant drugs
tranylcypromine, phenelzine, and isocarboxazid. The following foods contain relatively
high concentrations of tyramine and should be avoided by patients being treated with
an MAOI: fermented cheeses; imported beer; Chianti and some other wines;
champagne; soy sauce; avocados; bananas; overripe or spoiled food; and any
fermented, smoked, or aged fish or meat (such as salami, pepperoni, and bologna)
[66].

Patients considered to be at high risk for pheochromocytoma include:

● Familial pheochromocytoma – We suggest plasma fractionated metanephrines as the

best case-detection test in patients considered to be at high risk for pheochromocytoma
(high-risk familial syndromes such as MEN2 and VHL syndrome, previously surgically
resected pheochromocytomas or paragangliomas). A normal value excludes a
symptomatic catecholamine-secreting neoplasm but mildly elevated values of
 normetanephrine could be falsely positive, in which case we suggest doing 24-hour
urinary fractionated metanephrines, catecholamines, and imaging ( algorithm 1).

Special situations

● Kidney failure – Measurements of urinary catecholamines and metabolites may be invalid

if the patient has advanced kidney disease [67]. Serum chromogranin A levels have poor
diagnostic specificity in these patients [68]. In patients without pheochromocytoma who
are receiving hemodialysis, plasma norepinephrine and dopamine concentrations are
increased threefold and twofold above the upper limit of normal, respectively [69].
However, standard reference ranges can be used for interpreting plasma epinephrine
concentrations [70]. Therefore, when patients with kidney failure have plasma
norepinephrine concentrations more than threefold above the upper normal limit or
epinephrine concentrations greater than the upper normal limit, pheochromocytoma
should be suspected.

The findings of one study suggested that plasma concentrations of fractionated

metanephrines are increased approximately twofold in patients with kidney failure and
may be useful in the biochemical evaluation of patients with marked chronic kidney
disease or kidney failure [71]. However, the results from a different study suggested that
concentrations of plasma fractionated metanephrines could not distinguish between 10
patients with pheochromocytoma and 11 patients with end-stage kidney disease who
required long-term hemodialysis [72].

● Factitious pheochromocytoma – As with other similar disorders, factitious

pheochromocytoma can be very difficult to confirm [73,74]. The patient usually has a
medical background. The patient may "spike" the 24-hour urine container or the
catecholamines may be administered systemically [75,76].

ADDITIONAL EVALUATION AFTER BIOCHEMICAL DIAGNOSIS

Imaging — Biochemical confirmation of the diagnosis should be followed by radiological

evaluation to locate the tumor [1,7], not the other way around ( algorithm 1). Approximately
15 percent of the tumors are extra-adrenal, but 95 percent are within the abdomen and pelvis
[20]. Although any site containing paraganglionic tissue may be involved, the most common
extra-adrenal locations of catecholamine-secreting paragangliomas are the superior and
inferior abdominal paraaortic areas (75 percent of extra-adrenal tumors); the urinary bladder
(10 percent); the thorax (10 percent); and the skull base, neck, and pelvis (5 percent) [30].
CT and MRI

● Sporadic pheochromocytoma – CT or MRI of the abdomen and pelvis is usually performed

first. Either test is a reasonable first test as both detect almost all sporadic symptomatic
tumors because most are 3 cm or larger in diameter.

In sporadic pheochromocytoma, both CT and MRI are quite sensitive (98 to 100 percent)
but are only approximately 70 percent specific because of the higher prevalence of adrenal
"incidentalomas" (see "Evaluation and management of the adrenal incidentaloma"). The
choice between CT and MRI depends upon the cost and certain other factors described
below.

● With CT, there is some exposure to radiation but no risk of exacerbation of hypertension if
current radiographic contrast agents are given. CT with low-osmolar contrast is safe for
patients with pheochromocytoma even without alpha- or beta-adrenergic blocker
pretreatment, as illustrated in a report of 22 such patients [77]. After intravenous (IV) low-
osmolar contrast administration for CT scan, there was a significant increase in diastolic
blood pressure but no increase in plasma catecholamine levels or episodes of
hypertensive crises.

● With MRI, there is neither radiation nor dye. This more expensive test can distinguish
pheochromocytoma from other adrenal masses; on T2-weighted images,
pheochromocytomas appear hyperintense and other adrenal tumors isointense, as
compared with the liver ( image 1) [20]. However, MRI lacks the superior spatial
resolution of CT.

● Familial pheochromocytoma – In patients with the multiple endocrine neoplasia type 2

(MEN2) syndrome, computing imaging may miss approximately one-quarter of the tumors
[28]. In a selected group of patients with a 40 percent incidence of pheochromocytoma,
the respective positive and negative predictive values of CT were 69 and 98 percent [7].

● Imaging phenotype of pheochromocytoma/paragangliomas

• Increased attenuation on nonenhanced CT (most are >20 Hounsfield units [HU])

• Increased mass vascularity

• Delay in contrast medium washout (10 minutes after administration of contrast, an

absolute contrast medium washout of less than 50 percent)

• High signal intensity on T2-weighted MRI

 • Cystic and hemorrhagic changes

• Variable size and may be bilateral

Additional imaging — If abdominal and pelvic CT or MRI is negative in the presence of clinical
and biochemical evidence of pheochromocytoma, one ought to first reconsider the diagnosis. If
the diagnosis is still considered likely, a total body nuclear imaging study may be indicated.
These include: gallium-68 (Ga-68) DOTA-0-Phe1-Tyr-3 octreotate (gallium Ga-68 DOTATATE)-
positron emission tomography (Ga-68 DOTATATE PET); fludeoxyglucose-positron emission
tomography (FDG-PET); and iobenguane I-123 (diagnostic; also known as
metaiodobenzylguanidine [MIBG]) scintigraphy [78] .

Total body nuclear imaging is superfluous in patients with small sporadic solitary adrenal
pheochromocytoma identified on CT/MRI [79].However, it is indicated in patients with large (eg,
>8 cm) adrenal pheochromocytomas (increased risk of metastatic disease) or paraganglioma
(increased risk of multiple tumors and malignancy) ( image 2) [30].

68-Ga DOTATATE PET — Gallium-68 (Ga-68) DOTA-0-Phe1-Tyr-3 octreotate (gallium Ga-68

DOTATATE)-positron emission tomography (Ga-68 DOTATATE PET) is proving to be more sensitive
in some patients than iobenguane I-123, CT/MRI, or FDG-PET for detection of metastatic disease
( image 3) [80]. In addition, Ga-68 DOTATATE PET offers higher spatial resolution than
conventional 111-In pentetreotide scintigraphy. Ga-68 DOTATATE injection as a radioactive
diagnostic agent for PET imaging was approved by the US Food and Drug Administration (FDA)
in June 2016. A second radiotracer, gallium Ga-68 DOTATOC (DOTA-0-Phe1-Tyr3-octreotide;
where available) was approved in 2019 [81] and appears to have comparable diagnostic
accuracy to Ga-68 DOTATATE [82].

FDG-PET — Fludeoxyglucose-positron emission tomography (FDG-PET) is more sensitive

than iobenguane I-123 and CT/MRI for detection of metastatic disease ( image 4) [83-87]. The
utility of integrated FDG-PET/CT imaging as compared with iobenguane I-123 and conventional
cross-sectional imaging with CT or MRI was directly addressed in a prospective study of 216
patients with suspected pheochromocytoma/paraganglioma; 60 patients had nonmetastatic
disease, 95 had metastatic disease, and 61 did not have pheochromocytoma/paraganglioma
[84].

For the primary tumor, the sensitivity of PET/CT for nonmetastatic tumors was similar to that of
iobenguane I-123 but less than that of CT/MRI (77, 75, and 96 percent, respectively). Among the
patients who had paraganglioma/pheochromocytoma ruled out, specificity was comparable (90,
92, and 90 percent, respectively). When the analysis was limited to 26 paragangliomas of the
head and neck, PET/CT was more sensitive than iobenguane I-123 (85 versus 52 percent).
 Iobenguane I-123 — Iobenguane I-123 (diagnostic) is a compound resembling
norepinephrine that is taken up by adrenergic tissue. This scan can detect tumors not detected
by CT or MRI or multiple tumors when CT or MRI is positive [7].

Surgery is never indicated based on iobenguane I-123 findings alone; MIBG findings should
always be corroborated by findings on computed imaging. Normal adrenal glands take up
iobenguane I-123, and the uptake may be asymmetric.

Procedures to avoid

● Selective adrenal venous sampling (AVS) may result in inappropriate adrenalectomy.

When AVS for catecholamines was performed in 18 patients without pheochromocytoma,
epinephrine and norepinephrine concentrations were significantly higher in the right
versus the left adrenal vein (up to 83-fold difference for epinephrine) [88]. These data
highlight why AVS should not be used in the investigation of adrenal pheochromocytoma.

● Image-guided needle biopsy – Image-guided needle biopsy of suspected

pheochromocytoma or paraganglioma should be avoided due to a high rate of biopsy-
related complications. This was illustrated in a report of 20 patients who were diagnosed
at the time of needle biopsy, of whom 14 (70 percent) developed a biopsy-related
complication [89]. Complications included: increased difficulty of the definitive operation in
7 of 17 (41 percent) operative cases, with one patient requiring conversion to an open
procedure; severe hypertension (15 percent); hematoma (30 percent); incorrect or
inadequate biopsy (25 percent); severe pain (25 percent); and delay in surgical treatment
(15 percent) [89].

Genetic testing — Genetic testing should be considered in all patients with

pheochromocytoma or paraganglioma. Although most catecholamine-secreting tumors are
sporadic, approximately 40 percent have the disease as part of a familial disorder. In these
patients, the catecholamine-secreting tumors are more likely to be bilateral adrenal
pheochromocytomas or paragangliomas [6]. Genetic testing is usually performed
postoperatively after a pathologic diagnosis has been confirmed.

The familial disorders associated with pheochromocytoma (all of which have autosomal
dominant inheritance) include von Hippel-Lindau (VHL), MEN2, and neurofibromatosis type 1
(NF1). The approximate frequency of pheochromocytoma in these disorders is 10 to 20 percent
in VHL syndrome, 50 percent in MEN2, and 3 percent with NF1. These disorders are reviewed
separately. (See "Pheochromocytoma in genetic disorders".)
Germline pathogenic variants contributing to pheochromocytoma and paraganglioma have
three general transcription signatures: cluster 1, genes encoding proteins that function in the
cellular response to hypoxia; cluster 2, genes encoding proteins that activate kinase signaling;
and cluster 3, genes encoding proteins that are involved in Wnt signaling ( table 3). Cluster 1
tumors are mostly extra-adrenal paragangliomas (except in VHL, where most tumors are
localized to the adrenal), and nearly all have a noradrenergic biochemical phenotype [90]. In
contrast, cluster 2 tumors are usually adrenal pheochromocytomas with an adrenergic
biochemical phenotype. Cluster 3 tumors can have a noradrenergic or adrenergic biochemical
phenotype. Since 1990, at least 20 different pheochromocytoma/paraganglioma susceptibility
genes have been reported: NF1, RET, VHL, SDHD, SDHC, SDHB, EGLN1 (PHD2), EGLN2 (PDH1), KIF1B,
SDHAF2, IDH1, TMEM127, SDHA, MAX, HIF2A, and FH ( table 3) [84].

Most cases of familial paraganglioma are caused by pathogenic variants in the succinate
dehydrogenase (SDH; succinate:ubiquinone oxidoreductase) subunit genes (SDHB, SDHC, SDHD,
SDHAF2, SDHA). (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and
histology".)

The clinician may obtain a list of clinically approved molecular genetic diagnostic laboratories at
Genetic Testing Registry. The field of genetic testing is rapidly evolving, and at many clinical
laboratories, sequential genetic testing is no longer done, as it is less expensive to utilize next-
generation sequencing technology for all clinically available genetic variants as a package.
However, in those patients with neck and skull base paragangliomas, a case can be made for
obtaining an SDHx panel (to test for an SDHB, SDHC, SDHAF2, SDHA, or SDHD pathogenic
variants).

The approach to genetic testing is reviewed in more detail separately. (See "Paragangliomas:
Epidemiology, clinical presentation, diagnosis, and histology", section on 'Approach to genetic
testing'.)

PHEOCHROMOCYTOMA IN PREGNANCY

Paradoxical supine hypertension — Pheochromocytoma is a rare cause of hypertension

during pregnancy, with clinical features similar to those in the general population [91,92].
However, the supine position during pregnancy may allow the gravid uterus to compress the
tumor, causing paradoxical supine hypertension with normal blood pressure in the sitting or
erect position. Furthermore, if hypertension and proteinuria occur, pheochromocytoma may be
difficult to distinguish from preeclampsia.
Placental cells contain monoamine oxidase (MAO) and catechol o-methyl transferase (COMT),
which serve as a protective barrier for the fetus against excessive catecholamine exposure.
Thus, fetal loss associated with maternal pheochromocytoma is not a direct consequence of
maternal catecholamines acting on the fetus. However, the uteroplacental circulation is
responsive to alpha-adrenergic stimulation.

High concentrations of catecholamines induce marked vasoconstriction of the maternal uterine

arterial circulation, resulting in uteroplacental insufficiency, which may lead to spontaneous
abortion, fetal growth restriction, fetal hypoxia, and intrauterine fetal death. In addition,
paroxysmal hypertension may lead to placental abruption, and rebound hypotensive episodes
may lead to severe intrauterine hypoxia and adverse fetal outcomes [92].

As in nonpregnant women, the diagnosis is usually based upon the results of 24-hour urinary
fractionated metanephrines and catecholamines and plasma fractionated metanephrines. MRI
without gadolinium is the imaging test of choice in the pregnant woman. Stimulation tests and
iobenguane I-123 (also known as metaiodobenzylguanidine [MIBG]) scintigraphy are not
considered safe for pregnant women.

The early diagnosis of pheochromocytoma in the pregnant woman is key to preventing

morbidity and mortality. Before 1969, the fetal mortality rate due to maternal
pheochromocytoma was high (55 percent), with a slight difference between cases diagnosed
antepartum and those diagnosed postpartum (50 versus 57 percent, respectively) [93]. During
the period of 1969 to 1979, the overall fetal mortality was 47 percent (42 percent antepartum
diagnosis versus 56 percent postpartum diagnosis) [94]. Studies completed during the time
period of 1980 to 1987, reported that the fetal mortality rate decreased to 25 percent, and this
was markedly influenced by early diagnoses (12 versus 39 percent) [95]. During the time period
of 1987 to 2000, the overall fetal mortality rate decreased to 15 percent and the importance of
early diagnosis was confirmed (12 percent antepartum diagnosis versus 25 percent postpartum
diagnosis) [96].

In a multicenter retrospective study of patients with pheochromocytoma and pregnancy, 232

patients were identified who had a total of 249 pregnancies (1980 to 2019) while harboring a
catecholamine-secreting tumor [92]. The diagnosis of pheochromocytoma was made before (15
percent), during pregnancy (54 percent), or after delivery (31 percent). For patients diagnosed
antepartum, alpha-adrenergic blockade prevented adverse outcomes (odds ratio [OR] 3.6, 95%
CI 1.1-13.2), while antepartum surgery was not associated with better outcomes (no surgery
versus surgery OR 0.9, 95% CI 0.3-3.9). Unrecognized and untreated pheochromocytoma was
associated with a 27-fold higher risk of either maternal or fetal complications. Fetal death
occurred in 15 (7 percent) pregnancies and severe maternal complications or death in 13 (6
percent) pregnancies [92].

Medical therapy should be initiated with alpha-adrenergic blockade (either alpha-1 selective
with doxazosin or nonselective with phenoxybenzamine), followed, if necessary, by beta-
adrenergic blockade [97,98]. The timing of surgical intervention, which may be performed
laparoscopically for adrenal neoplasms, is more controversial. Some authors recommend
surgery if the fetus is previable (less than 24 weeks of gestation) and medical management
when the pregnancy is further along [99-102]. The rationale for surgery is that
phenoxybenzamine crosses the placenta, and reports of perinatal depression and transient
hypotension have been described [100]. However, phenoxybenzamine has generally been safe
for the fetus [97].

In patients managed medically during pregnancy, cesarean section can be followed by tumor
resection a few weeks later after uterine involution [103]. Spontaneous labor and delivery
should be avoided. Cesarean section is the preferred mode of delivery since it appears to carry
less risk of maternal death than vaginal delivery [97]. The management of catecholamine-
secreting paragangliomas in pregnancy may require modification of these guidelines
depending on tumor location [104].

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Adrenal incidentaloma"
and "Society guideline links: Pheochromocytoma and paraganglioma".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics."
The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading
level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer
short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more
sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print
or e-mail these topics to your patients. (You can also locate patient education articles on a
variety of subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topics (see "Patient education: Pheochromocytoma (The Basics)")

SUMMARY AND RECOMMENDATIONS

● Epidemiology – Most catecholamine-secreting tumors are sporadic. However,

approximately 40 percent of patients have the disease as part of a familial disorder; in
these patients, the catecholamine-secreting tumors are more likely to be bilateral adrenal
pheochromocytomas or multiple paragangliomas. (See 'Epidemiology' above.)

● Clinical presentation – Symptoms are present in approximately 50 percent of patients

with pheochromocytoma, and when present, they are typically paroxysmal. (See
'Symptoms and signs' above.)

● Diagnostic testing – The diagnosis of pheochromocytoma is made based upon

biochemical confirmation of catecholamine hypersecretion, followed by identifying the
tumor with imaging studies. Many patients are tested for possible sporadic
pheochromocytoma, but few will ultimately be diagnosed with the disorder (approximately
1 in 300). (See 'Indications for testing' above.)

• Biochemical evaluation – We suggest initial biochemical testing based upon the index
of suspicion that the patient has a pheochromocytoma. If there is a low index of
suspicion, we suggest 24-hour urinary fractionated catecholamines and
metanephrines; if there is a high index of suspicion, we suggest plasma fractionated
metanephrines ( algorithm 1). Medications that can interfere with results are
reviewed above ( table 1). (See 'Discontinue interfering medications' above and
'Initial biochemical tests' above.)

For patients with biochemical confirmation of the diagnosis, the next step is radiologic
evaluation to locate the tumor. (See 'Positive case-detection test' above.)

• Imaging – Biochemical confirmation of the diagnosis should be followed by radiologic

evaluation to locate the tumor [60,62], not the other way around ( algorithm 1). In
sporadic pheochromocytoma, CT or MRI of the abdomen and pelvis is usually
performed first. Either test detects almost all sporadic tumors because most are 3 cm
or larger in diameter. (See 'CT and MRI' above.)
 If CT or MRI is negative in the presence of clinical and biochemical evidence of
pheochromocytoma, one ought first to reconsider the diagnosis. If it is still considered
likely, then total body nuclear imaging with Gallium-68 (Ga-68) DOTA-0-Phe1-Tyr-3
octreotate (gallium Ga-68 DOTATATE)-positron emission tomography (68-Ga DOTATATE
PET), fludeoxyglucose-positron emission tomography (FDG-PET), or iobenguane I-123
(also known as metaiodobenzylguanidine [MIBG]) scintigraphy may be done; these
scans can detect tumors not detected by CT or MRI. (See '68-Ga DOTATATE PET' above
and 'FDG-PET' above and 'Iobenguane I-123' above.)

• Genetic testing – Genetic testing should be considered in all patients with

pheochromocytoma or paraganglioma. (See 'Genetic testing' above.) ( table 3)

● Pheochromocytoma in pregnancy – Pheochromocytoma is a rare cause of hypertension

during pregnancy, with clinical features similar to those in the general population. The
approach to diagnosis is the same as for nonpregnant women. Maternal and fetal
mortality rates are high, particularly in those who are not diagnosed until delivery. Alpha-
adrenergic blockade is associated with fewer adverse outcomes. (See 'Pheochromocytoma
in pregnancy' above.)

ACKNOWLEDGMENTS

The views expressed in this topic are those of the author(s) and do not reflect the official views
or policy of the United States Government or its components.

The UpToDate editorial staff acknowledges Norman M Kaplan, MD, who contributed to earlier
versions of this topic review.

Use of UpToDate is subject to the Terms of Use.

Topic 130 Version 52.0

GRAPHICS

Medications that may increase measured levels of catecholamines and

metanephrines

Tricyclic antidepressants

Levodopa

Drugs containing adrenergic receptor agonists (eg, decongestants)

Amphetamines

Buspirone and most psychoactive agents

Prochlorperazine

Reserpine

Withdrawal from clonidine and other drugs

Ethanol

Graphic 80180 Version 3.0

Evaluation and treatment of catecholamine-producing tumors

68-Ga DOTATATE PET: gallium 68 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-octreotate; CT:

computed tomography; FDG: fluorodeoxyglucose; Met: metanephrine; MRI: magnetic resonance
imaging; Nmet: normetanephrine; PET: positron emission tomography.

Modified and reprinted with permission from: Young WF Jr. Pheochromocytoma: 1926-1993. In: Trends in Endocrinology and
Metabolism, vol 4, Elsevier Science, Inc 1993. p.122.

Graphic 81154 Version 9.0

Differential diagnosis of pheochromocytoma-type spells

Endocrine

Pheochromocytoma
"Hyperandrenergic spells"
Thyrotoxicosis
Primary hypogonadism (menopausal syndrome)
Medullary thyroid carcinoma
Pancreatic tumors (eg, insulinoma)
Hypoglycemia
Carbohydrate intolerance

Cardiovascular

Labile essential hypertension

Cardiovascular deconditioning
Pulmonary edema
Syncope
Orthostatic hypotension
Paroxysmal cardiac arrhythmia
Angina
Renovascular disease

Psychologic

Anxiety and panic attacks

Somatization disorder
Hyperventilation
Factitious (eg, drugs, valsalva)

Pharmacologic

Withdrawal of andernergic-inhibitor
MAOI treatment plus decongestant
Sympathomimetic ingestion
Illegal drug ingestion (cocaine, PCP, LSD)
Chlorpropamide-alcohol flush
Vancomycin flushing syndrome

Neurologic

POTS
Autonomic neuropathy
Migraine headache
 Diencephalic epilepsy (autonomic seizures)
Stroke
Cerebrovascular insufficiency

Other

Unexplained flushing spells

Mast cell disease
Carcinoid syndrome
Recurrent idiopathic anaphylaxis

LSD: lysergic acid diethylamide; MAOI: monoamine oxidase inhibitor; PCP: phencyclidine; POTS: postural
orthostatic tachycardia syndrome.

Reproduced with permission from: Young WF Jr. Pheochromocytoma and primary aldosteronism. Cancer Treat Res 1997; 89:239.
Copyright © 1997 Springer Science and Business Media.

Graphic 63617 Version 5.0

Pheochromocytoma in the adrenal gland

MRI findings in adrenal pheochromocytomas.

(A) Sagittal MRI demonstrates a mass (arrow) displacing the inferior vena cava anteriorly (arrowhead).
This caval displacement is typically seen with tumors arising in the adrenal gland.

(B) Coronal MRI of the abdomen demonstrates a large mass in the right adrenal bed (arrow), lying
immediately superior to the kidney. The low signal intensity in the center is caused by hemorrhage into
the tumor.

MRI: magnetic resonance imaging.

Courtesy of Jonathan Kruskal, MD.

Graphic 56897 Version 4.0

Diffuse metastatic pheochromocytoma

123-I MIBG scan from a 41-year-old female shows diffuse metastatic pheochromocytoma.

123-I: iodine-123; MIBG: metaiodobenzylguanidine.

Courtesy of William F Young, Jr, MD.

Graphic 73899 Version 5.0

Comparison of 123-I MIBG versus 68-Ga DOTATATE PET CT in detecting
metastatic pheochromocytoma

123-I MIBG scan (A) from a 61-year-old female shows diffuse metastatic pheochromocytoma. 68-Ga-
DOTATATE PET CT total body coronal image (B) and sagittal image (C) from the same patient and during
the same episode of care.

123-I MIBG: iodine-123 metaiodobenzylguanidine; 68-Ga DOTATATE PET: gallium 68 1,4,7,10-

tetraazacyclododecane-1,4,7,10-tetraacetic acid-octreotate positron emission tomography.

Courtesy of William Young, Jr, MD, MSc.

Graphic 116935 Version 2.0

FDG-PET scan showing diffuse metastatic paraganglioma

FDG-PET scan from a 28-year-old female shows a diffuse metastatic paraganglioma (coronal image on
left and sagittal image on right).

FDG: fludeoxyglucose; PET: positron emission tomography.

Courtesy of William F Young, Jr, MD.

Graphic 59671 Version 5.0

Germline mutations associated with pheochromocytoma and paraganglioma

Typical tumor location and other

Syndrome/name Gene
associations

Pseudo-hypoxic – Cluster 1 *

SDHD mutation (familial SDHD Primarily skull base and neck;

paraganglioma type 1) ¶ occasionally adrenal medulla,
mediastinum, abdomen, pelvis; GIST;
possible pituitary adenoma

SDHAF2 mutation (familial SDHAF2 Primarily skull base and neck;

paraganglioma type 2) ¶ occasionally abdomen and pelvis

SDHC mutation (familial SDHC Primarily skull base and neck;

paraganglioma type 3) occasionally abdomen and pelvis; GIST;
possible pituitary adenoma

SDHB mutation (familial SDHB Abdomen, pelvis and mediastinum;

paraganglioma type 4) rarely adrenal medulla, skull base, and
neck; GIST; possible pituitary adenoma

SDHA mutation SDHA Primarily skull base and neck;

occasionally abdomen and pelvis; GIST;
possible pituitary adenoma

VHL disease VHL Adrenal medulla, frequently bilateral;

occasionally paraganglioma that may be
localized from skull base to pelvis

Hereditary leiomyomatosis and renal FH Multifocal and metastatic; associated

cell carcinoma (Reed syndrome) – with hereditary leiomyomatosis, uterine
Fumarate hydratase mutation fibroids, and renal cell cancer

Hypoxia inducible factor 2-alpha EPAS1 (HIF2A) Paraganglioma, polycythemia, and rarely
somastostatinoma

Familial erythrocytosis associated EGLN2 Polycythemia associated with

with mutation in prolyl hydroxylase pheochromocytoma and paraganglioma
isoform 1 (PDH1)

Familial erythrocytosis associated EGLN1 Polycythemia associated with

with mutation in prolyl hydroxylase pheochromocytoma and paraganglioma
isoform 2 (PDH2)

Kinesin Family Member 1B gene KIF1B Neuroblastoma

DNA methyltransferase 3-alpha gene DNMT3A Skull base and neck paraganglioma

Dihydrolipoamide S- DLST PGL7 tumor predisposition syndrome;

succinyltransferase gene pheochromocytoma and thoraco-
 abdominal paragangliomas

Succinate-CoA ligase GDP-forming SUCLG2 Paraganglioma

subunit beta gene

Kinase signaling pathway – Cluster 2 Δ

MEN2A and MEN2B RET Adrenal medulla, frequently bilateral

Neurofibromatosis type 1 NF1 Adrenal or peri-adrenal

MAX ¶ MAX Adrenal medulla

Familial pheochromocytoma TMEM127 Adrenal medulla; possible renal cell

carcinoma

HRAS proto-oncogene, GTPase HRAS

Wnt signaling pathway – Cluster 3 ◊

Cold shock domain E1 CSDE1 Sporadic, aggressive disease with

frequent recurrence and metastases

UBTF (Upstream Binding Transcription UBTF::MAML3 fusion Sporadic, aggressive disease with
Factor) fusion with MAML3 frequent recurrence and metastases
(mastermind like transcriptional
coactivator 3)

GIST: gastrointestinal stromal tumor; MEN2: multiple endocrine neoplasia type 2; SDH: succinate
dehydrogenase; VHL: von Hippel-Lindau.

* Cluster 1 tumors are mostly extra-adrenal paragangliomas (except in VHL, where most tumors are
localized to the adrenal), and nearly all have a noradrenergic biochemical phenotype.

¶ Associated with maternal imprinting.

Δ Cluster 2 tumors are usually adrenal pheochromocytomas with an adrenergic biochemical phenotype.

◊ Cluster 3 tumors can have a noradrenergic or adrenergic biochemical phenotype.

Original figure modified for this publication. Young WF. Endocrine hypertension. In: Williams Textbook of Endocrinology, Melmed
S, Polonsky KS, Larsen PR, Kronenberg HM (Eds), 13th ed, Elsevier Inc, Philadelphia 2015. p.556. Table used with the permission of
Elsevier Inc. All rights reserved.

Graphic 106549 Version 3.0

