The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 8 2903-2906
Copyright © 2000 by The Endocrine Society
Corticotropin-Independent Cushing’s Syndrome Caused by an Ectopic Adrenal Adenoma
Alejandro R. Ayala,
Shehzad Basaria,
Robert Udelsman,
William H. Westra and
Gary S. Wand
Department of Medicine, Division of Endocrinology (A.R.A., S.B.,
G.S.W.), Department of Surgery (R.U.), and Department of Pathology
(W.H.W.), The Johns Hopkins University School of Medicine, Baltimore,
Maryland 21205
Address all correspondence and requests for reprints to: Gary S. Wand, M.D., Department of Medicine, The Johns Hopkins University School of Medicine, Ross Research Building, Room 863, 720 Rutland Avenue, Baltimore, Maryland 21205.
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Abstract
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Although nonsecreting suprarenal embryonic remnants are frequently
found in the urogenital tract, adenomatous transformation resulting in
glucocorticoid excess is a rare phenomenon. We report a case of a
63-yr-old woman that presented with new-onset hirsutism, facial
plethora, hypertension, centripetal obesity, and a proximal myopathy.
The 24-h urinary free cortisol excretion rate was elevated, and the
serum ACTH level was suppressed. The patient failed an overnight and
low dose dexamethasone suppression test and did not respond to CRH
stimulation. In light of the undetectable baseline morning ACTH levels
and the blunt response to CRH, the diagnosis of
corticotropin-independent Cushing’s syndrome was made. Imaging studies
revealed normal adrenal glands and enlargement of a left pararenal
nodule incidentally observed 4 yr before the onset of symptoms.
Dramatic resolution of symptoms was observed after surgical removal of
the 3.5-cm mass. Pathological exam confirmed adrenocortical adenoma in
ectopic adrenal tissue. The case reported here represents the unusual
circumstance in which the development of adenomatous transformation of
ectopic adrenal tissue has been prospectively observed with imaging
studies. It illustrates the importance of considering ectopic
corticosteroid-secreting tumors in the context of
corticotropin-independent Cushing’s syndrome.
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Introduction
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HETEROTOPIC adrenal tissue can be found
along the embryological migration path of the adrenal glands, mainly in
the area of the celiac axis. The vast majority of the cases reported in
the literature are represented by nonsecreting (hormonally inactive)
ectopic adrenal accessory tissues. Under rare circumstances, after
bilateral adrenalectomy (presumably under corticotropin stimulation),
corticosteroid-secreting heterotrophic adrenal tissue may cause
Cushing’s syndrome. We report the case of a woman with intact adrenal
glands who presented with spontaneous corticotropin-independent
Cushing’s syndrome caused by an ectopic adrenal adenoma. In doing so,
we review the pertinent literature and emphasize the importance of
considering this rare entity in the differential diagnosis of the
glucocorticoid excess syndrome.
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Case Report
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A 63-yr-old woman developed hirsutism and moderate hypertension 1
yr before presentation. She had gained 9 kg and complained of easy
bruisability associated with fatigue and generalized weakness,
predominantly involving the proximal musculature of the extremities.
She denied headaches or vision loss. Physical examination revealed
facial plethora, centripetal obesity, and the presence of darkened
terminal hair on the superior lip, side burns, abdomen, and forearms.
She had required treatment with short courses of oral corticosteroids
for chronic bronchitis, which were discontinued 2 yr before
presentation. The past medical history was otherwise relevant for
osteopenia and a pelvic fracture resulting from minor trauma. She had a
history of spastic colon. A computed tomography (CT) scan of the
abdomen obtained 4 yr before the onset of the above symptoms revealed a
small nodular structure of undetermined significance in the left renal
hilum (Fig. 1
). She had
hypercholesterolemia, Hashimoto’s thyroiditis, and hypothyroidism,
which was adequately treated with levothyroxine. Screening tests for
Cushing’s syndrome included a morning cortisol level of 690 nmol/L
(normal, <138) obtained after a 1-mg overnight dexamethasone
suppression test. The 24-h urinary free cortisol (determined by high
performance liquid chromatography) was 358.8 nmol/day (normal, <138
nmol/day) after a 2-day low dose (2 mg/day) dexamethasone suppression
test. An ovine CRH stimulation test (1 mg/kg) revealed an early morning
baseline ACTH level of less than 0.22 pmol/L (normal, 1.98–11.44) with
a peak ACTH level of 0.484 pmol/L at 90 min. Further laboratory
evaluation revealed a serum total testosterone level of 6.90 nmol/L
(normal, 0.17–1.74) and a dehydroepiandrosterone level of 0.81
µmol/L (normal, 0.8–7.04). The routine serum biochemical profile was
otherwise unremarkable, including liver and kidney function tests. In
light of the undetectable baseline morning ACTH levels and the blunt
response to CRH, the diagnosis of corticotropin-independent Cushing’s
syndrome was made. The differential diagnosis included primary
micronodular adrenal hyperplasia, corticosteroid abuse, and an ectopic
glucocorticoid-secreting adrenal tumor. Both a contrast CT scan and
magnetic resonance imaging of the abdomen revealed significant
enlargement of the previously noted left pararenal lesion interpreted
as an ureteral tumor adjacent to the hilum and measuring approximately
3.5 cm (Fig. 2, A and B). There
was no evidence of ureteral obstruction. Both adrenal glands were
normal in size. An iodocholestrol scan was negative. Incidentally, a
2-cm speculated left lower lobe lung nodule was observed. Because the
patient had been a heavy smoker, a wedge resection of the pulmonary
nodule was performed. Histopathology revealed a hypocellular area with
dense fibrosis and scarring suggestive of a remote infection or infarct
without evidence of malignancy. The possibility of an ectopic pulmonary
cortisol- and testosterone-secreting tumor was therefore excluded after
surgical removal of the lung nodule. The patient was examined, and the
left kidney was mobilized. The mass was intimately associated with the
left renal vein, but was easily excised without evidence of invasion or
ureteral involvement. A complete resection of the left pararenal mass
was performed. The postoperative course was uncomplicated. She was
discharged home on glucocorticoids.
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Figure 1. CT scan of the abdomen performed 4 yr before
the onset of symptoms, showing a small nodular lesion near the left
renal hilum (arrow).
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Figure 2. Recent CT (A) and MRI (B) of the abdomen
showing growth in the lesion seen in Fig. 1 (arrow). The
nodule was approximately 3.5 cm in diameter.
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The resection specimen consisted of an oval nodule surrounded by a rim
of fat. The nodule weighed 7 g and measured 3.5 cm. On cut
section, the nodule was unencapsulated but sharply circumscribed,
without infiltration of the surrounding fat. The cut surface was solid,
homogenous, and dark brown (Fig. 3). By
light microscopy, the tumor was composed of broad fields of pink cells
arranged in nests and interconnecting trabeculae (Fig. 4, A and B). The cells had uniform
round nuclei with prominent nucleoli. Their cytoplasm was abundantly
pink and granular and contained pigmented granular material
representing lipofuscin. Mitotic activity was very low, and there was
no evidence of necrosis or invasive tumor growth. Nonneoplastic adrenal
tissue was not apparent. Ultrastructurally, the cells were remarkable
for abundant smooth endoplasmic reticulum, large stacks of rough
endoplasmic reticulum, and mitochondria containing tubulovesicular
cristae. These pathological features are very characteristic of an
adrenal cortical adenoma associated with Cushing’s syndrome. Due to
the intracellular accumulation of lipofuscin, tumors associated with
Cushing’s syndrome are often darkly pigmented. When this pigmentation
is diffuse, as in our case, they are sometimes referred to as "black
adenomas" of Cushing’s syndrome.
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Figure 3. Gross appearance of ectopic adrenocortical
adenoma. Typical of black adenoma associated with Cushing’s syndrome,
the cut surface is darkly pigmented.
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Figure 4. Histological features of ectopic
adrenocortical adenoma. A, The tumor cells are arranged in nests and
trabeculae (hematoxylin and eosin stain; magnification, x160). B, The
black coloration seen grossly is due to the presence of abundant
intracytoplasmic lipofuscin (Kinyoun’s stain; magnification, x630).
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Nine months after surgery, the serum ACTH levels remained suppressed
(<0.22 pmol/L). A repeat CT scan of the abdomen failed to reveal
recurrence of the tumor. The adrenal glands were normal in size.
Complete cure was documented by persistently low early morning cortisol
levels requiring hydrocortisone supplementation and by a 24-h urinary
free cortisol level of 63.4 nmol/day. The hirsutism, facial plethora,
and centripetal obesity have resolved. The total serum testosterone
level fell to 0.69 nmol/L. Mild hypertension persists.
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Discussion
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Aberrant or ectopic adrenocortical tissue is frequently
found in children, but is less common in adults (1). The majority of
the cases reported in the literature are represented by nonsecreting
remnants found along the path of embryonic migration within the
urogenital tract (2). Adrenal cortical rests have been found in the
testis, spermatic cord (3), broad ligament, kidney, retrocaval space
(4), and celiac region. Less frequently, they can be found in the
lungs, (5) central nervous system (6), and gastrointestinal tract
(colon, pancreas, and gallbladder). A comprehensive review of the
literature revealed that accessory and heterotopic adrenal tissue was
most commonly found in the area of the celiac axis (32%) followed by
the broad ligament (23%), adenexa of testes (7.5%), and spermatic
cord (3.8–9.3%). Accessory adrenal tissue was found in the kidney in
only 0.1–6% of the cases reviewed, predominantly located in the
subcapsular area of the upper pole (7).
Tumoral transformation of ectopic embryonic rests resulting in
adrenal carcinomas (8) or adenomas is an exceedingly uncommon
phenomenon. Moreover, the pathophysiology of adrenocortical
tumorigenesis is poorly understood. Cytokines (interleukin-5 and -6)
and growth factors that under normal conditions play a role in
physiological paracrine regulation of the adrenal cortex have been
implicated in this process. Some tumors may express aberrant or ectopic
receptors as well as activating mutations of G protein-coupled
receptors resulting in cortisol, aldosterone, and gonadal steroid
hypersecretion. (9)
There are few cases in the literature of ectopic adrenocortical
neoplasms causing Cushing’s syndrome. Ney et al. (10)
reported the case of a man who continued to have Cushing’s syndrome
after bilateral adrenalectomy. During surgical exploration, a
cortisol-secreting tumor was found in the retrohepatic space. Leibowitz
et al. (11) recently reported recurrence of Cushing’s
syndrome in a 33-yr-old-woman with an ectopic adrenocortical adenoma.
The patient had undergone a total left adrenalectomy for a left adrenal
gland adenoma 4 yr before recurrence.
In this case, we report the development of glucocorticoid excess
4 yr after radiographic documentation of a left pararenal tumor,
strongly suggesting that the tumor arose from displaced cortical
adrenal tissue. The embryological relationship between the adrenal
cortex and the urogenital ridge explains the location of the tumor.
Given the paucity of reports describing similar cases, the rate of
neoplastic transformation of adrenocortical embryonic remnants is
probably very low. In any extent, ectopic adrenal adenomas should be
considered in the context of corticotropin-independent Cushing’s
syndrome when the adrenal glands appear normal or when symptoms recur
after adrenalectomy (12, 13). Although complete resolution of the
symptoms was observed in our case, we believe that periodic biochemical
screening for Cushing’s syndrome as well as repeat imaging studies on
a yearly basis would represent a prudent approach.
In summary, cortisol-secreting adrenal adenomas arising from ectopic
adrenocortical embryonic remnants are rare, and early detection is only
possible when a high index of suspicion is present. Furthermore, early
detection is partially responsible for the increase in survival rates
observed in patients with sustained endogenous hypercortisolism (14).
The case we report represents the unusual circumstance in which the
sequential development and adenomatous transformation of ectopic
adrenal tissue have been documented with serial imaging studies.
Complete resolution of endogenous glucocorticoid excess with minimal
therapeutic morbidity, as observed in this case, is seldom achieved. It
is therefore important to consider ectopic corticosteroid-secreting
tumors in the context of corticotropin-independent Cushing’s
syndrome.
Received December 2, 1999.
Revised February 25, 2000.
Accepted March 22, 2000.
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Abstract
Introduction
