Clinician Update
Pheochromocytoma
A Devious Opponent in a Game of Hide-and-Seek
Neelam H. Shah, MD; Daniel T. Ruan, MD
Case 1
M.G. is a 53-year-old woman with a his-
tory of episodic flushing, hypertension,
and an incidentally discovered adrenal
mass who presented with shortness of
breath, weakness, and lightheadedness
in the setting of hypertension to 300/200
mm Hg. Physical examination revealed
an obese woman with a systolic ejection
murmur and bibasilar crackles, but no
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neurological or ophthalmologic signs
of hypertension. Plasma metanephrines
were 0.50 nmol/L (normal: 0–0.49
nmol/L) and normetanephrines were
1.8 nmol/L (normal: 0–0.89 nmol/L);
24-hour urine epinephrine was 10 μg
(normal: 0–20 μg) and norepinephrine
was 119 μg (normal: 15–80 μg; Table).
Autonomous hyperaldosteronism and
hypercortisolism were excluded. Renal
artery ultrasound was unremarkable;
T2-weighted abdominal MRI revealed a
2.5 × 1.8 centimeter hypointense lesion
in the right adrenal gland (Figure 1A).
Presumed diagnosis was pheochro-
mocytoma, for which appropriate pre-
operative preparation and surgery, as
described later, were conducted.
Case 2
J.C. is a 30-year-old woman with
a history of pregnancy-induced
From the Department of Medicine (N.H.S.) and the Endocrine Surgical Unit (D.T.R.), Brigham & Women’s Hospital, Boston, MA; the Department of
Medicine, Boston Children’s Hospital, Boston, MA (N.H.S.); and the Department of Pediatrics, Boston Medical Center, Boston, MA (N.H.S.).
Correspondence to Daniel T. Ruan, 75 Francis Street, Boston, MA 02115. E-mail druan@partners.org
(Circulation. 2014;130:1295-1298.)
© 2014 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
hypertension who presented with
abdominal pain, vomiting, and bloody
diarrhea. Physical examination was
notable for normal vital signs and
a mildly uncomfortable appearing
woman with a systolic ejection mur-
mur and diffusely tender abdomen.
Plasma metanephrines were 0.31
nmol/L, and normetanephrines were
11.7 nmol/L; 24-hour urine epineph-
rine was 18 μg, and norepinephrine
was 804 μg (Table). T2-weighted
abdominal MRI revealed a 36-mm
heterogeneous left adrenal mass
(Figure 1B). Presumed diagnosis was
pheochromocytoma, for which appro-
priate preoperative preparation and
surgery were conducted.
Background
Pheochromocytoma, a catecholamine
secreting mass located in the adrenal
gland, is a rare but often fatal cause
of hypertension. Annual incidence is
2 to 8 cases per million, but outpa-
tient screening studies for secondary
hypertension estimate a prevalence of
0.2% to 0.6%, primarily in the third
through fifth decades, with no sex
difference.1–10 Periodically-secreted
catecholamines cause paroxysms
of headache, flushing, palpitations,
DOI: 10.1161/CIRCULATIONAHA.114.008544
1295
diaphoresis, anxiety, tremors, and
severe hypertension that can rapidly
lead to fatal stroke, arrhythmia, and
myocardial infarction. Hypertension
may be paroxysmal or persistent, and
some patients may be normotensive
as a result of hypovolemia, increased
production of endogenous vasodi-
lators, or downregulation of α-1
adrenergic receptors.1,11 The diagno-
sis is suspected in patients with epi-
sodic symptoms, a family history of
the tumor, hypertension at a young
age, idiopathic dilated cardiomyopa-
thy, variable blood pressures, known
suprarenal mass, adverse cardiovascu-
lar response to anesthesia, or refrac-
tory hypertension.11,12
Work-Up
The biochemical work-up of pheo-
chromocytoma begins with the mea-
surement of serum catecholamine
metabolites (metanephrines and
normetanephrines) and a 24-hour col-
lection of urine catecholamines (epi-
nephrine and norepinephrine), both
of which are at least quadrupled in
most patients with pheochromocy-
toma. Normal levels in a hypertensive
symptomatic patient make the diagno-
sis unlikely but do not exclude it in a
 1296  Circulation  October 7, 2014

Table. Serum and Plasma Catecholamine Metabolite Values definitive biochemical exclusion of
pheochromocytoma.
Normal M.G. J.C. Pheochromocytoma
Plasma 0–0.49 nmol/L 0.50 nmol/L 0.31 nmol/L >1.5 nmol/L
metanephrines
Treatment
Definitive treatment is surgical removal
Plasma 0–0.89 nmol/L 1.8 nmol/L 11.7 nmol/L >2.7 nmol/L
after preoperative α- and β-blockade to
normetanephrines
prevent intraoperative crises. Preferred
24-hour urine 0–20 μg 10 μg 18 μg >80 μg
epinephrine
preparation is a 2-week course of
phenoxybenzamine or doxazosin with
24-hour urine 15–80 μg 119 μg 804 μg >240 μg
norepinephrine
progressive dosage escalation until the
patient is orthostatic, but calcium chan-
nel blockers are also effective.2,11 A lib-
normotensive asymptomatic patient.1 with equivocal imaging or a genetic eral salt diet and fluid boluses are used
Borderline results (<3-fold the upper predisposition for extra-adrenal or to counteract vasodilation-induced vol-
limit of normal) warrant repeat mea- multifocal tumors, functional imaging ume contraction and orthostatic symp-
surement after 30 minutes of supine such as 123I-MIBG (iodine-131-meta- toms. Intraoperatively, fluid boluses
rest (Figure 2).11 iodobenzylguanidine) scintigraphy is after isolation of the tumor are often
Elevated laboratory markers warrant appropriate. necessary to treat α-blockade-induced
anatomic imaging of the abdominal/ When imaging is negative and hypotension.11 Sodium nitroprusside
pelvic region; patients with atypical medications or anxiety are the most may be necessary for crisis-related
presentations may require more exten- likely cause of mild catecholamine hypertension, although lidocaine and
sive imaging (Figures 1 and 2).1 CT elevation, clonidine suppression test- beta blockers can be used to treat
and MRI are equally sensitive in ing can sometimes exclude pheochro- tachyarrhythmias.11
detecting pheochromocytoma, which mocytoma. Percutaneous biopsy may When feasible, endoscopic adre-
is bright on T2-weighted MRI and vas- cause a dangerous surge of catechol- nalectomy, using the laparoscopic or
cular on contrast CT.1,2,11,13 For patients amines and should not be used before
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retroperitoneoscopic approaches, are

preferred because they are associated
with reduced mortality and length of
stay. However, open adrenalectomy
through a thoracoabdominal approach
may be necessary for large or locally
invasive tumors.2,14–17 Postoperatively,
biochemical surveillance is recom-
mended to screen for recurrent or per-
sistent disease. Frequent screening CT
or MRI scans are unnecessary if bio-
chemical tests remain negative.2

Pheochromocytoma
Imposters
Pheochromocytoma is a potentially
lethal cause of hypertension and
important to rule out in a hyperten-
sive patient. However, the condition is
rare, and false positives on biochemi-
cal testing and imaging are common.
In fact, 97% of hypertensive patients
with elevated plasma fractionated
metanephrines will not have pheo-
chromocytoma, but may still receive
imaging and potentially inappropri-
ate surgery.2,18 Hence, it is necessary
to exclude other causes of elevated
catecholamine levels before initiating
Figure 1. M.G. and J.C. Imaging. A, M.G: Abdominal MRI. B, J.C: Abdominal MRI. treatment (Figure 2).11
 Shah and Ruan   Challenges in the Diagnosis of Pheochromocytoma   1297

Figure 2. Work-up of suspected pheochromocytoma. Algorithm only applies if there is diagnostic uncertainty with a strong plausible
alternative diagnosis. If pheo is the leading diagnosis and delaying treatment could be harmful, imaging and surgery should not be
delayed for further testing. Also note that pheo specifically refers to tumors that begin in the adrenal glands; extra-adrenal tumors with
the characteristics described here are paragangliomas and not discussed here. Alternative explanations can include medications (tricyclic
antidepressants, minoxidil, hydralazine, labetalol, buspirone, acetaminophen), substance abuse (cocaine), anxiety, withdrawal (clonidine,
alcohol), or medical problems (acute myocardial infarction/ischemia, New York Heart Association Class III or IV heart failure). Functional
imaging: I123-MIBG scintigraphy. Extra-adrenal imaging: inferior para-aortic areas, bladder, thorax, head, neck, pelvis. Pheo indicates
pheochromocytoma.

Incidentally discovered adrenal pheochromocytoma symptoms, and References

masses are also common, occurring in she was hypertensive only during preg- 1. Bravo EL, Tagle R. Pheochromocytoma:
4% to 6% in the general population, and nancy, a time when hypertension is state-of-the-art and future prospects. Endocr
Downloaded from http://ahajournals.org by on November 16, 2018

as many as 70% of patients aged >70
years.19 Though most adrenal masses
are benign, they cannot be ignored, as
10% to 15% of them may be malignant
or functional.19 Hence, although pheo-
chromocytoma must be ruled out in a
symptomatic and hypertensive patient
with known adrenal mass, other causes
of hypertension and adrenal mass, such
as an aldosterone-secreting tumor,
should also be considered.
Both M.G. and J.C. had adrenal inci-
dentalomas. M.G. had many classic
pheochromocytoma findings, includ-
ing hypertensive emergency and flush-
ing, in the setting of elevated urine
and serum markers. Though her signs
and symptoms were classic for pheo-
chromocytoma, close evaluation of her
biochemical studies and MRI hinted
that she did not have a pheochromocy-
toma. Her plasma metanephrine level
was only twice the upper limit of nor-
mal, and the mass was not particularly
hyperintense on T2-weighted images.
Ultimately, pathology confirmed her
mass to be an adrenal adenoma, not a
pheochromocytoma.
J.C.’s history, on the other
hand, was negative for any classic
common. However, her biochemical
markers were diagnostic of pheochro-
mocytoma, with a serum normeta-
nephrine and urine norepinephrine >10
times the upper limit of normal. The
hyperintense mass on her MRI was also
consistent with this diagnosis, and sur-
gical pathology ultimately confirmed
her mass to be a pheochromocytoma.
Comparing these cases demonstrates
not only how well pheochromocytoma
can disguise itself, but also how well
adrenal adenomas can mimic pheo-
chromocytoma, particularly given the
nonspecific symptoms often seen in
perimenopausal women. The juxtapo-
sition of these cases should serve as a
call to have both a low threshold to con-
sider pheochromocytoma as a potential
diagnosis in a hypertensive patient and
also a discerning mind to realize that
not all seemingly classic stories will
actually be pheochromocytoma.
Sources of Funding
This work was supported by American
Cancer Society grant MRSG-13-062-01.
Disclosures
None.
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