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Annales d’Endocrinologie 79 (2017) 75–81

Clinical case

Secreting ectopic adrenal adenoma: A rare condition to be aware of


Adénome surrénalien sécrétant : une rareté qu’il faut connaître
Yang Zhao a , Hui Guo a , Ying Zhao b , Bingyin Shi a,∗
a Department of Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong, University School of Medicine, Xi’an, Shannxi 710061, PR China
b Department of Pathology, The First Affiliated Hospital of Xi’an Jiaotong, University School of Medicine, Xi’an, Shannxi 710061, PR China

Abstract
Ectopic adrenal adenoma causing chronic Cushing’s syndrome (CS) is a rare phenomenon. Diagnosis is usually made years after disease onset
because of the insidious nature of the ectopic adrenal gland and because it overlaps with common symptoms, such as overweight and hypertension,
in the general population (Kreitschmann-Andermahr et al., 2015). Here, we report the case of a 46-year-old male with a 15-year history of severe
hypertension, facial plethora, and centripetal obesity. During treatment for herpes zoster, the patient presented with severe hypokalemia and flaccid
paralysis, characteristic changes associated with CS. The serum cortisol level was elevated and baseline adrenocorticotrophic hormone (ACTH) was
suppressed. After administration of the low-dose overnight dexamethasone suppression test, plasma cortisol was 38.9 ␮g/dL. A contrast computed
tomography (CT) scan revealed normal adrenal glands and significant tumor adjacent to the right renal hilum measuring ∼ 3.6 × 2.3 cm. The tumor
was removed through retroperitoneoscopy, and pathological examination confirmed adrenocortical adenoma and myelolipoma metaplasia. The
serum potassium level gradually became normal after surgical removal of the mass. In the current report, we have reviewed the pertinent literature
and highlighted the importance of considering ectopic adrenal adenoma in the differential diagnosis of chronic CS with nonspecific symptoms.
© 2017 Elsevier Masson SAS. All rights reserved.

Keywords: Cushing’s syndrome; Ectopic adrenal adenoma; Differential diagnosis

Résumé
L’adénome surrénal ectopique, responsable du syndrome de Cushing (CS), est un phénomène rare. Le diagnostic est habituellement posé des
années après l’apparition de la maladie en raison du caractère insidieux que revêt la glande surrénale ectopique et parce qu’il se chevauche avec
des symptômes assez banals, comme le surpoids et l’hypertension, en population générale. Nous rapportons ici le cas d’un homme de 46 ans
avec 15 années d’antécédents d’hypertension artérielle sévère, de phénotype pléthorique et d’obésité centripète. À l’occasion d’un traitement
pour de l’herpès, le patient a présenté une hypokaliémie et une paralysie flasque, symptômes pouvant évoquer un hypercorticisme. Le taux de
cortisol plasmatique était augmenté et l’hormone adrénocorticotrophique de base (ACTH) était abaissé. Après administration de dexaméthasone
pendant la nuit, le cortisol plasmatique du matin restait élevé à 38,9 ␮g/dL. Unscanner abdominal a révélé des glandes surrénales normales
et une tumeur située dans le hile rénal droit mesurant 3,6 × 2,3 cm. La tumeur a été retirée par rétropéritonéoscopie, et l’examen pathologique a
confirmé l’adénome adrénocortical associéà une métaplasie de type myélolipome. Le taux de potassium sérique est progressivement devenu normal
après élimination chirurgicale de la masse. Dans cet article, nous rapportons la revue de la littérature et soulignons l’importance de considérer
l’éxistence d’un adénome surrénalien ectopique dans le diagnostic différentiel d’un hypercorticisme devant des symptômes frustres.
© 2017 Elsevier Masson SAS. Tous droits réservés.

Mots clés : Syndrome de Cushing ; Hypercorticisme ; Adénome surrénal ectopique ; Diagnostic différentiel

∗ Corresponding author.
E-mail address: shibingy@126.com (B. Shi).

https://doi.org/10.1016/j.ando.2017.03.003
0003-4266/© 2017 Elsevier Masson SAS. All rights reserved.
76 Y. Zhao et al. / Annales d’Endocrinologie 79 (2017) 75–81

1. Case report obesity, muscle atrophy of limbs, and muscle strength grade
of 3+. Blood pressure was determined as 148/86 mmHg. The
A 46-year-old man was admitted to our hospital in January long-term high cortisol level was associated to osteopenia and
2016, because of CS presenting with hypokalemia and flaccid multiple destruction of the rib cage. The patient had developed
paralysis. During the past fifteen years, the patient gained signif- tuberculosis two years before but recovered after administration
icant weight, characterized as centripetal obesity, and developed of anti-tuberculous chemotherapy. Based on the collective clin-
severe hypertension with extremely high blood pressure reach- ical symptoms and laboratory results, a diagnosis of CS was
ing 190/130 mmHg. He took Adalat GITS 30 mg daily in the made.
morning to control his blood pressure, that fluctuated between The patient was admitted to our hospital to determine the
120/70 and 160/100 mmHg, but did not focus on his other symp- cause of CS. The serum cortisol level showed an abnor-
toms. Two years ago, the patient suffered from intracerebral mal rhythm, with an early morning baseline ACTH level
hemorrhage, leaving a sequelae of muscle weakness in right of < 1.00 pg/mL (normal values: 5.0–60.0 pg/mL). The morn-
upper extremity. Furthermore, he was diagnosed with herpes ing plasma cortisol level was 37.2 ␮g/dL before and 38.9 ␮g/dL
zoster based on severe pain and rash around the right intercostal (normal values: 5.0–28.0 ␮g/dL) after the administration of
skin. During anti-viral treatment, he complained of generalized dexamethasone 1.0 mg overnight. In light of the undetectable
weakness and fatigue predominantly involving the proximal baseline morning ACTH and low dexamethasone suppression
musculature of the extremities, inability to walk and turn test, the patient was diagnosed with corticotropin-independent
over, and easy bruisability of skin. Consequently, a screening Cushing’s syndrome. A contrast CT scan disclosed a significant
test for CS was performed at the hospital, which showed a tumor mass adjacent to the right renal hilum of ∼ 3.6 × 2.3 cm
morning plasma cortisol level of 881.5 nmol/L (normal values: in size (Fig. 2). The mass was intimately associated with the
171–536 nmol/L). The low-dose overnight dexamethasone sup- right ureter. Both adrenal glands were normal in size (Fig. 2).
pression test revealed a plasma cortisol level of 1005.0 nmol/L. Laparoscopic operation facilitated removal of the adrenal tumor
No increase in the plasma concentrations of testosterone and including right kidney because of hemorrhage of the blood vessel
dehydroepiandrosterone sulfate was observed. The serum potas- during tumor separation (Fig. 3).
sium level was low at 2.2 mmol/L before supplementation. The The resection specimen consisted of a quasi-circular nodule
glycated hemoglobin level was 5.90%but oral glucose toler- surrounded locally by a thin film. A 3.5 × 2.5 × 2 cm mass with
ance test disclosed impaired glucose tolerance (IGT). Metabolic an irregular and lobulated shape was observed in the renal portal
alkalosis was detected via blood gas analysis. Computed tomo- fibrous adipose tissue. Microscopically, tumor cells comprised a
graphy revealed a right para-adrenal mass and normal size of mixture of zona glomerulosa and zona fasciculata cells arranged
both adrenal glands. in a nest-like, alveolar, fasciculate form. We observed no necro-
The patient had no complaint of headaches, vision loss, sis and nuclear division, and nuclear morphology was consistent.
polyuria, polydipsia or polyphagia. Physical examination The pathological diagnosis was adrenocortical adenoma with
revealed facial plethora, moon face (Fig. 1A), marked centripetal myelolipoma metaplasia (Fig. 4). We detected a small number

Fig. 1. Cushingoid appearance before and after surgery. A. The patient with facial plethora, moon face. B. Same patient’s appearance after removal of ectopic adrenal
in 6 months.
Y. Zhao et al. / Annales d’Endocrinologie 79 (2017) 75–81 77

Fig. 4. Histological features of ectopic adrenal adenoma. The tumor cells com-
prised a mixture of zona glomerulosa and zona fasciculata cells arranged in a
Fig. 2. Abdominal enhancement computed tomography (CT) scan showing
nest-like, alveolar, fasciculate form.
a significant tumor mass adjacent to the right renal hilum with a size of
∼ 3.6 × 2.3 cm (arrow).

Fig. 5. The Ki-67 proliferation index of the ectopic adrenal adenoma was about
3%.

level. Over a half-year period postoperatively, blood pressure


was gradually decreased and Cushingoid appearance relieved
(Fig. 1B). However, during this time, the patient suffered from
acute cholecystitis, cerebral infraction and lumbar fracture.
These conditions were potentially attributable to existing vas-
cular and fracture lesions caused by long-term hypercortisolism
Fig. 3. Gross appearance of the resection specimen. A 3.5 × 2.5 × 2 cm tumor
with an irregular and lobulated shape was observed in the renal portal fibrous
and hypertension being further triggered by other stress factors.
adipose tissue.
2. Discussion
of lymphocytes and focal myeloid lipoma within the tumor. The
Ki-67 proliferation index was about 3% (Fig. 5). Cushing’s syndrome (CS) is a relatively rare disease affect-
Postoperatively, treatment with exogenous corticosteroids ing 2–5 million individuals per year, although establishing
was initiated due to adrenal atrophy because of long-term inhi- definitive and differential diagnosis of CS remains a signifi-
bition of ACTH. The dosage was gradually reduced to 30 mg cant clinical challenge. The overall diagnostic process from first
hydrocortisone daily. One month after discharge, the patient symptoms to definite diagnosis takes 3.8 years (median of 2.0
had regained much of his strength and could walk gradually. years) on average [1]. In the current case, the patient devel-
The blood cortisol level was determined as 163.80 nmol/L (nor- oped severe hypertension and central obesity 15 years before
mal values: 7–10 am 171–536 nmol/L; 4–8 pm 64–327 nmol/L) presentation. He was admitted to hospital twice for treatment
and blood potassium without supplementation was 3.4 mmol/L, of cerebral hemorrhage and tuberculosis, but did not raise any
which was significantly increased, compared to preoperative concerns about the relationship of symptoms to CS until the
Table 1

78
Characteristics of the 8 ectopic adrenal tumor cases.
CaseAuthor Year Location Clinical sings Biology Treatment Pathology Outcome

Plasma cortisol Urinary free ACTH Potassium level Identification


cortisol

1 Raith and Karl 1969 Cranial of the left Hypertrichosis Plasma 11- – – 3.4 Surgical Surgery Malignant Symptoms
adrenal gland of the face and hydroxycorticosteroid intervention Irradiate with gradually
extremities, was within normal cobalt improved
oligomenor- range (19 ␮g%),
rhea and increased to
49 ␮g% after
stimulation with
corticotropin
2 Contreras et al. 1985 Posterior segment Amenorrhea, 0800 h 40.8 ␮g/dL 1627 mg/24 h – 3.3 Ultrasonogram An experimental Benign Symptoms
of the right lobe of central (normal values (normal values and CT of the trial with gradually
the liver obesity, severe 8–25 ␮g/dL) 20–100 mg/24 h) abdome, ketoconazole improved

Y. Zhao et al. / Annales d’Endocrinologie 79 (2017) 75–81


hirsutism, 500 h 48.5 ␮g/dL anaortography Surgery
diffuse scalp (normal
hair loss, values < 6 ␮g/dL)
fatigue, 2300 h 47.7 ␮g/dL
muscle (normal
weakness, and values < 6 ␮g/dL)
exertional
dyspnea
3a Adeyemi et al. 1986 Right ovarian Blindness, Morning cortisol – – – Ultrasonogram Surgery Benign Symptoms
aphasia and 47 ␮g/dL (normal and surgical gradually
inability to 7–14 ␮g/dL); intervention improved
move the right night cortisol
arm and leg, 38 ␮g/dL (normal
hypertension, 5–9 ␮g/dL)
precocious
pseudopu-
berty, features
of Cushing
syndrome
4 Leibowitz et al. 1998 The area of the Gain weight, Morning cortisol 115 mg/24 h < 20 pg/mL – CT scan and NP53 Surgery Benign Symptoms
left adrenal gland cervical-dorsal 18.1 ␮g/dL; an scan gradually
fat pad, overnight 1 mg improved
amenorrhea, dexamethasone
muscle suppression test
weakness and revealed a plasma
fatigue cortisol level of
6.9 ␮g/dL
5 Ayala et al. 2000 Left renal hilum Hirsutism, Morning cortisol 358.8 nmol/day < 0.22 pmol/L – CT scan and Surgery Benign Symptoms
facial plethora, level of (normal, (normal, magnetic gradually
hypertension, 690 nmol/L 138 nmol/day) 1.98–11.44 pmol/L) resonance imaging improved
centripetal (normal < 138) after a 2-day
obesity, and a obtained after a low-dose
proximal 1 mg overnight (2 mg/day)
myopathy dexamethasone dexamethasone
suppression test suppression test
Table 1 (Continued)
CaseAuthor Year Location Clinical sings Biology Treatment Pathology Outcome

Plasma cortisol Urinary free ACTH Potassium level Identification


cortisol

6 Jain et al. 2008 Testicular Bilateral Morning cortisol 3216 nmol/day Undetectable 2.9 Testicular Orchiectomy; Malignant Died from
testicular level of (normal ultrasound and mitotane and progres-
masses, lower 1269 nmol/L range < 138 nmol/day) abdominal CT metyrapone sion and
extremity (normal values scans (decrease cortisol complications

Y. Zhao et al. / Annales d’Endocrinologie 79 (2017) 75–81


edema, and 138–552 nmol/L) production) of poorly
cushingoid controlled
appearance, hypercortisoism
muscle
weakness,
hypertension
7 Louiset et al. 2010 Left renal hilum Aciotruncal 730 nmol/L 2190 nmol/day; 1.1 pmol/L – Abdominal CT Surgery (retroperi- Benign Symptoms
obesity, facial (normal: (normal: (normal: and toneoscopy) gradually
erythrosis, 250–50 0nmol/L) 55–220 nmol/day) 2.2–17.6 pmol/L) noriodocholesterol improved
easy bruising, in the morning; scintigraphy
striae, 666 nmol/L at
hypertension, midnight
and
amenorrhea
8 Yang Zhao et al. 2016 Right renal hilum Centripetal 8:00 h – < 1.00 pg/mL 2.2–2.7 Abdominal CT Surgery Benign Symptoms
obesity, 33.89 ␮g/dL (normal, and renal gradually
hypertension, (normal values 5–60 pg/mL) angiography improved
weakness and 5–28 ␮g/dL)
fatigue, easy 16:00 h
bruising 30.7 ␮g/dL
(normal
values < 6 ␮g/dL)
24:00 h
24.9 ␮g/dL
(normal
values < 6 ␮g/dL)
a The patient is a 2-year-old girl. Others are all adults.

79
80 Y. Zhao et al. / Annales d’Endocrinologie 79 (2017) 75–81

attack of herpes zoster. Accordingly, we speculate that pain but used to confirm the presence of an adrenal remnant after
stress or drugs containing glucocorticoid exacerbate long-term bilateral adrenalectomy [17].
hypercortisolism. Our patient had severe hypokalemiaranging from
Ectopic adrenal gland is the residual tissue during the course 2.2–2.7 mmol/L. And indeed Cushing’s syndrome is one of the
of adrenal migration in embryonic development commonly common causes of hypokalemia, but obvious hypokalemia or
detected in fetuses and children but rarely found in adults associated alkalosis mainly occur in ectopic ACTH syndrome
[2]. With advancing age and the presence of normal adrenal and adrenal cortical adenocarcinoma. Hypokalemia is reported
gland, the majority of ectopic adrenal glands undergo atro- in 90% of ectopic ACTH syndrome cases. While only 10%
phy. Consequently, the incidence rate of ectopic adrenal gland hypokalemia occurs in Cushing’s syndrome, Cushing’s disease
in adults is only 1% [3,4]. Adrenal cortex is derived from accounts for only ∼ 2%, while adrenal cortical adenoma is
the mesothelial cell population located between the mesenteric commonly not associated to hypokalemia [18,19]. Ectopic
root of the posterior abdominal wall and urinary genital ridge adrenal adenoma resulting in severe hypokalemia has rarely
and adrenal medulla from the sympathetic ridge. With medulla been documented. Among the 7 cases of ectopic adrenocortical
cell migration into the fetal adrenal cortex region, fragments neoplasm, only Jain et al. [14] reported a 65-year-old man
of adrenal tissues, especially those of the adrenal cortex, may with severe hypokalemia (2.0 mmol/L).However, in this case,
split out. The majority of fragments remain in the vicinity of Cushing’s syndrome was attributable to an adrenocortical
the normal adrenal gland, but some that are associated more carcinoma that was developed within the paratesticular tissue.
closely with the urinary genital ridges may shift with migra- Finally, the main treatment goals in patients with cortisol-
tion of the developing gonads [5]. Ectopic adrenal gland was producing ectopic adrenal tumors are to remove the tumor for
initially described by Morgagni in 1740, at the University of restoring the normal function of hypothalamo-pituitary-adrenal
Bologna. Since then, considerable research has focused on the axis. Cortisol is one of the most essential hormones in humans,
presence of ectopic adrenal gland during surgery or autopsy, which functions to increase blood sugar through gluconeogen-
with most reported cases of residual adrenal cortex in the esis, suppress the immune system, and aid in the metabolism of
testis, spermatic cord, broad ligament, kidney, retrocaval region fat, protein, and carbohydrates. Based on the above findings, it is
and abdominal cavity. Occasional cases have additionally been recommended that patients who are hypocortisolaemic, because
detected in the lung, central nervous system, and gastrointestinal of central ACTH inertia in the immediate postoperative period
tract [6]. should receive glucocorticoid treatment until the axis recovers
The majority of case reports in the literature are non- full activity, that requires usually 6–18 months after surgery [19].
functional ectopic adrenal while secreting remnants are infre-
quent. Very few patients with ectopic adrenal tumors develop 3. Conclusion
pathophysiological changes that result in ACTH-independent
Cushing’s syndrome, cortical carcinoma, aldosteronism, and We report a rare case of Cushing’s syndrome with severe
neuroblastoma [7–9]. Chaffee et al. [10] originally reported a hypokalemia attributable to ectopic adrenal adenoma. This
patient with Cushing’s syndrome who had undergone bilateral case highlights the importance of focusing on overlapping and
adrenal resection without relief of symptoms. Exploratory oper- chronic symptoms of the general population, such as hyper-
ation revealed a mass of 7 cm × 2 cm × 1 cm located in the lower tension, to facilitate more timely diagnosis. Additionally, our
pole of the left kidney. Histological examination showed hyper- findings suggest that ectopic adrenal adenoma can induce
plasia of adrenal cortex, speculated to be due to stimulation of hypokalemia. Surgical excision is usually effective in relieving
ectopic adrenal hyperplasia resulting from increased patholog- chronic Cushing’s syndrome and hypokalemia in patients with
ical ACTH level after bilateral adrenal gland resection. While ectopic adrenal adenoma.
no experimental evidence has been obtained with human sub-
jects, Jaffe et al. confirmed the above finding in mice. In their Disclosure of interest
study, accessory adrenal or ectopic adrenal hyperplasia was iden-
tified in a quarter of mice subjected to bilateral adrenal complete The authors have not supplied their declaration of compet-
resection [3]. ing interest. And this research received no specific grant from
To date, only 7 cases of cortisol-producing ectopic adreno- any funding agency in the public, commercial, or not-for-profit
cortical neoplasms with Cushing’s syndrome have been reported sectors.
[6,11–16], localized in the adrenal areas, liver, ovary, and the
pararenal region. The method employed to detect ectopic adrenal References
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