Adrenal

1. A R T I C L E
An Adrenal Incidentaloma Diagnosed as
Dopamine-Secreting Pheochromocytoma:
A Case Report
Jing Jing, M.D., Minmin Yu, M.D., Bo Jiang, M.D., Ph.D.
Acknowledgments: The authors wish to express their gratitude to the patient
who participated in this study.
Abstract: Background: Dopamine-secreting pheochromocytomas are
exceedingly rare.
Case presentation: A 28-year-old woman, who was admitted due to 4 hours of
acute-onset abdominal pain, detected an adrenal mass incidentally. She was
almost asymptomatic without a known family history. Laboratory assessments
showed significant increases in dopamine levels of serum and 24-h urinary. By
using preoperative a-adrenergic receptor blockers, she developed orthostatic
hypotension and palpitations. When she underwent laparoscopic left
adrenalectomy, she experienced rapid cyclic fluctuations in systolic blood
pressure from 90 mmHg to 200 mmHg. Postoperatively, she exhibited prolonged
hypotension, requiring vasopressor therapy and fluid replacement. According to
histopathological diagnosis, it was a pheochromocytoma. Dopamine levels in
24-h urine and serum decreased to normal after operation. Analysis of specific
gene SDHB, SDHD, RET, VHL and NF1 detected no pathogenic mutations.
Conclusion: Patients with dopamine-secreting pheochromocytomas are mostly
asymptomatic, leading to a significant delay in diagnosis. There is a large
possibility for dopamine-secreting pheochromocytomas to show a malignant
tendency than the adrenergic and noradrenergic phenotypes. The a-
adrenergic receptor blocker is not indicated for preoperative medical
treatment because it can cause hypotension and cardiovascular failure.
Calcium channel blockers or metyrosine may be better alternatives. All patients
with pheochromocytomas should receive targeted genetic testing based on
specific clinical features. SDHB, SDHD, RET, VHL and NF1 mutations are suggested
for genetic testing of adrenal dopamine-secreting pheochromocytomas.
Abbreviations: PASS, pheochromocytoma of the adrenal gland scaled score;
VMA, vanillylmandelic acid
Keywords: Pheochromocytoma-Dopamine-a-Adrenergic receptor blocker-
Genetic testing-Adrenal incidentaloma
Author affiliations: Jing Jing, Department of Endocrinology, Qingdao Municipal Hospital,
Qingdao, Shandong 266071, China; Minmin Yu, Department of Endocrinology, Qingdao
Municipal Hospital, Qingdao, Shandong 266071, China; Bo Jiang, Department of Urology,
Qingdao Municipal Hospital, Qingdao, Shandong 266071, China
Correspondence: Bo Jiang, M.D., Ph.D., Department of Urology, Qingdao Municipal
Hospital, Qingdao, Shandong 266071, China., email: jiangboqdy@126.com
ª 2020 by the National Medical Association. Published by Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.jnma.2020.07.005
INTRODUCTION
P
heochromocytomas are rare tumors, which originate
from chromaffin cells of the parasympathetic or
sympathetic paraganglia and produce excess
amounts of one or more catecholamines: epinephrine,
norepinephrine and dopamine. The most common symp-
toms are either sustained or paroxysmal episodes of
hypertension, headache, palpitations and perspiration.
However, patients with pheochromocytoma have a wide
variety of nonspecific symptoms, which makes it chal-
lenging for physicians to make a timely diagnosis. Nearly
20% of patients with incidentally discovered adrenal
masses on imaging studies prove to have a pheochromo-
cytoma.1
According to the biochemical characteristics,
pheochromocytomas can be divided into three major
phenotypes: the adrenergic, noradrenergic and dopami-
nergic phenotypes which are defined by predominant ele-
vations in epinephrine, norepinephrine and dopamine
respectively. We report a case with a dopamine-secreting
pheochromocytoma that is extremely rare and almost
asymptomatic. This phenotype differs from another phe-
notypes in many respects, including clinical features,
preoperative medical treatment and genetic testing. This
case report provides some implications for the manage-
ment of dopamine-secreting pheochromocytomas.
CASE REPORT
A 28-year-old woman was admitted due to 4 hours of
nausea vomiting and acute-onset abdominal pain.
Computed tomography of the abdomen revealed a
5 4 4 cm mass in the left adrenal region with necrosis
(Figure 1). She suffered 1-3 episodic palpitations per
month, and each time lasted for 10-20 minutes. There was
no history of hypertension or other symptoms suggestive of
catecholamine excess. She had no positive family history.
She was 160 cm tall and weighed 54 kg. Her body tem-
perature was 36.8
C and blood pressure was 103/59 mmHg
respectively, with a heart rate of 72 beats/minute. Abdom-
inal examination showed a soft abdomen, no tenderness, no
palpable masses and no ascites. Her bowel sounds were
normal. The results of laboratory tests, including a complete
blood count, liver and renal function tests and serum elec-
trolytes, were all unremarkable.
Serum normetanephrines, 3.2 nmol/l (0.0-0.9) and
metanephrines levels, 1.2 nmol/l (0.0-0.5) were all mildly
elevated. After analyzing a sample of 24-h urine, we
discovered a marked rise of dopamine level of
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2. urinarye2265.9 mg/day (0.0-600.0), which is different
from the normal levels of norepinephrine, epinephrine and
vanillylmandelic acid (VMA). A severely elevated serum
dopamine level, 2890.0 pmol/l (0.0-210.0 pmol/l) was also
found. A dopamine-secreting pheochromocytoma was
corresponding to our preoperative diagnosis in the left
adrenal gland containing a large necrosis.
Laparoscopic left adrenalectomy was recommended to
our patient. The dose of doxazosin as preoperative medical
treatment was titrated to 4 mg/day, however, the medica-
tion stopped because palpitations and orthostatic hypo-
tension were developed in the patient. During tumor
resection, there were rapid cyclic fluctuations in systolic
blood pressure from 90 mmHg to 200 mmHg. Post-
operatively, the patients developed prolonged hypotension,
requiring vasopressor therapy and fluid replacement for
36 hours.
Gross pathology revealed 7 4 4 cm mass attached
to adrenal gland. There was extensive coagulative necrosis
in the center of the tumor. A large number of hemosiderin-
containing macrophages and histiocytes were observed
around the necrotic area, accompanied by vascular pro-
liferation. The cytoplasm of these tumor cells positive for
chromogranin A was immunohistochemically, synapto-
physin and tyrosine hydroxylase, which supported the
diagnosis of pheochromocytoma. The pheochromocytoma
of the Adrenal gland Scaled Score (PASS) was 2 points
(one point for nuclear pleomorphism, and one point for
hyperchromasia), the highest score was 20 points. A PASS
of 4 for pheochromocytomas have a greater risk of
malignant potential (Figure 2).
A stepwise analysis of specific gene SDHB, SDHC and
SDHD was undertaken. No pathogenic mutations were
detected. Her serum and 24-h urine dopamine, norepi-
nephrine, epinephrine and VMA levels returned to normal
after the operation. The overall situation was good, and no
recurrence occurred during the follow-up for one year.
This work was carried out in accordance with 1975
Declaration of Helsinki Principles. The study was
approved by The Institutional Review Board and The
Ethics Committee of the hospital. Informed consent for
publishing the work was signed by the patient.
DISCUSSION
Pheochromocytoma arises from chromaffin cells of extra-
adrenal paraganglia and the adrenal medulla, which usu-
ally secretes norepinephrine and epinephrine. Typical
manifestations are perspiration, headache, palpitations and
either sustained or paroxysmal episodes of hypertension.
Pheochromocytoma, which predominantly produces
dopamine with negligible or only mild increases in the
norepinephri ne and epinephrine levels, is extremely rare.
Our patient was a young female patient who manifested up
to 4 hours of acute-onset abdominal pain and palpitations.
Imaging studies exhibited a large adrenal pheochromocy-
toma. Our patient underwent laparoscopic adrenalectomy,
and we can confirm it is a dopamine-secreting pheochro-
mocytoma by observing remarkably high levels of serum
and urinary dopamine and immunohistochemistry. A large
coagulative necrosis of the tumor can be observed by light
microscopic examination. Patients with predominantly
dopamine-secreting pheochromocytomas are mostly
asymptomatic. In addition, nonspecific clinical presenta-
tion as hypotension, fever, weight loss, irritating cough,
nausea, vomiting, chronic diarrhea or abdominal pain may
occur.2,3
Lack of identifiable symptoms may lead to a significant
delay in diagnosis. The dopamine-secreting pheochromo-
cytomas are ascribed to reducing levels of the enzyme
dopamine b-hydroxylase, which can help dopamine
convert to norepinephrine. That deficiency results in
dopamine accumulation and a decreased production of
epinephrine, norepinephrine and their end product,
VMA.4,5
There is a big possibility for dopamine-secreting
pheochromocytomas to show the malignant tendency
than the adrenergic and noradrenergic phenotypes. It is
reported that the malignancy rate of Dopamine-secreting
pheochromocytomas is 66%-90%, while the malignant
rate of adrenergic and noradrenergic phenotypes is
21%-29%.6,7
Reducing levels of the dopamine b-hydrox-
ylase are associated with higher malignancy rates and poor
differentiation of pheochromocytomas. Besides, extra-
adrenal location, DNA aneuploidy or triploidy, high
levels of 24-h urinary dopamine, persistent postoperative
hypertension and a tumor of more than 80 g have been
correlated with higher rates of malignancy and large tumor
size.8,9
However, malignant and benign pheochromocy-
tomas cannot be reliably distinguished by histopathologic
features. In order to diagnose malignant pheochromocy-
tomas, the only way is the detection of metastatic lesions.
In the follow-up to the diagnosis of persistent diseases, it is
crucial to measure urine levels plasma of metanephrines
and implement lifelong annual biochemical testing
throughout life to assess metastatic or recurrent disease.5,10
It is routinely recommended that all patients with a
hormonally functional pheochromocytoma should undergo
preoperative blockade to prevent perioperative cardiovas-
cular complications due to catecholamine release during
surgical manipulation. The a-adrenergic receptor blockers
are considered the first choice. However, different from the
adrenergic and noradrenergic phenotype, patients with
dopamine-secreting pheochromocytomas who receive
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JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL 113, NO 1, FEBRUARY 2021 47

3. pre-operative a-adrenergic receptor blockers reportedly
develop severe hypotension and cardiovascular collapse
both intra- and postoperatively.4
It is attributed to the
deficiency of norepinephrine and epinephrine. This effect
is accentuated by the stimulation of D2 receptors located
on the presynaptic membranes of sympathetic ganglia
which inhibits the release of norepinephrine.11
Alpha-
receptors cannot attract dopamine. Dopamine exerts its
vasodilatory effects by working on D1 receptors located on
vascular smooth muscle cells. The non-antagonistic
hypotension effect of dopamine was significant when
catecholamines are blocked, which led to some authors to
recommend the use of a-adrenergic receptor blockers in
patients with pheochromocytomas who secrete only
dopamine. However, in patients who did not receive
a-adrenergic receptor blockers, severe intraoperative hy-
pertension requiring nicardipine may occur. It may be
appropriate for patients with dopamine-secreting to use
shorter-acting a-adrenergic receptor blockers cautiously in
a shorter preoperative period, considering the fact that drug
resistance, intraoperative uncontrolled hypertension
resulting in severe and irreversible cardiovascular and
neurovascular damage and, the fact that hypotension is
usually more sensitive to treatment.12
Because of ortho-
static hypotension, the traditional blood pressure targets
may not be tolerated, it is necessary to increase slow
dosage and monitor carefully. In addition, the Endocrine
Society guidelines and the AACE Adrenal Scientific
Committee also recommend calcium channel blockers as
monotherapy in only certain situations or first-line therapy
for preoperative management respectively.13,14
Metyrosine
may also be an alternative, since it inhibits tyrosine con-
verting to dopamine and has no a-blocking effects. Using
metyrosine preoperatively reportedly decreases intra-
operative hemodynamic lability and causes postoperative
cardiovascular complications.15,16
Our patient developed
orthostatic hypotension and palpitations because of taking
doxazosin and prolonged hypotension postoperatively.
The patient still experienced hemodynamic instability
during surgical manipulation. Considering calcium chan-
nel blockers or metyrosine, a loosened blood pressure
target may be more appropriate.
Fig. 2. Histopathological findings of the resected left adrenal gland. (A) Gross appearance of the cut surface of the left adrenal tumor showed the inferior
surface to be necrotic. (B and C) Hemorrhagic and fibrotic components within adrenal medulla mass. (B-E) Immunohistochemical staining: CD56 (þ);
CgA (þ); Syn (þ); Ki-67 (), confirming the diagnosis of pheochromocytoma.
Fig. 1. Computed tomography scan shows hypervascular mass with
dimensions of 5 4 cm on left adrenal gland with early washout
enhancing pattern.
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4. Biochemical properties of pheochromocytomas are
attributed to the underlying genetic mutation which in-
fluences differentiation of tumor progenitor cells, cate-
cholamine biosynthetic enzymes, secretory pathways and
epigenetic remodeling profiles. Nearly 40% of pheochro-
mocytomas and paragangliomas have been attributed to
germline mutations.17
Given this high frequency of genetic
mutations, all patients with pheochromocytomas should
accept genetic screening.13
Pheochromocytomas and par-
agangliomas of the dopaminergic phenotype have reduced
levels of the enzyme dopamine b-hydroxylase. This
finding may be resulted from proliferation of poorly
differentiated progenitor cells, as seen in patients with
metastatic disease as well as SDHB and SDHD muta-
tions.18
Patients with these mutations show increases in
dopamine levels. SDHB, SDHD, RET, VHL and NF1
mutations are suggested for genetic testing of adrenal
dopamine-secreting pheochromocytomas.14
No pathogenic
mutations in our patient were detected.
All in all, Dopamine-secreting pheochromocytomas are
exceedingly rare. Patients with these tumors are mostly
asymptomatic, resulting in a significant delay in diagnosis.
There is a big possibility for dopamine-secreting pheo-
chromocytomas rather than the adrenergic and noradren-
ergic phenotypes to show malignant tendency. In the
follow-up to the diagnosis of persistent diseases, it is
crucial to measure urine levels plasma of metanephrines
and implement lifelong annual biochemical testing
throughout life to assess metastatic or recurrent disease.
The a-adrenergic receptor blocker is not indicated for
preoperative medical treatment, because it can cause hy-
potension and cardiovascular failure. Calcium channel
blockers or metyrosine may be an alternative. All patients
with pheochromocytomas should undergo targeted genetic
testing based on specific clinical features. SDHB, SDHD,
RET, VHL and NF1 mutations are suggested for adrenal
dopamine-secreting pheochromocytomas.
FUNDING SOURCES
This research did not receive any specific grant from
funding agencies in the public, commercial, or not-for-
profit sectors.
FINANCIAL DISCLOSURE:
The authors declare that they have no conflict of interest.
AVAILABILITY OF DATA AND
MATERIALS:
The datasets used and/or analyzed during the current study
are available from the corresponding author on reasonable
request.
CONFLICT OF INTEREST
Conflict of interest: The authors declare that they have no
conflict of interest.
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