Vičić et al.

CASE REPORT

Recurrence of Cushing’s disease after

bilateral adrenalectomy: A myth or reality?
Ivan Vičić1, Ivan Kruljac2, Miroslav Ćaćić2, Jelena Marinković Radošević2, Gorana Mirošević2, Hrvoje Ivan Pećina3,
Vatroslav Čerina4, Leo Pažanin5, Milan Vrkljan1,2

1
School of Medicine, University of Zagreb, Zagreb, Croatia
2
Department of Endocrinology, Diabetes and Metabolic Diseases “Mladen Sekso,” University Hospital Center “Sestre Milosrdnice,” Zagreb, Croatia
3
Department of Radiology, University Hospital Center “Sestre Milosrdnice,” Zagreb, Croatia
4
Department of Neurosurgery, University Hospital Center “Sestre Milosrdnice,” Zagreb, Croatia
5
Department of Pathology, “Ljudevit Jurak,” University Hospital Center “Sestre Milosrdnice,” Zagreb, Croatia

Corresponding author: Abstract

Ivan Kruljac, Department of Endocrinology,
Diabetes and Metabolic Diseases “Mladen
Sekso,” University Hospital Center “Sestre
Milosrdnice,” University of Zagreb Medical
School, Vinogradska Cesta 29, 10000
Zagreb, Croatia, Tel.: 00385992179089,
e-mail: ivkruljac@gmail.com
DOI: 10.21040/eom/2017.3.3.6
Received: July 23rd 2017
Accepted: August 30th 2017
Published: September 29th, 2017
Copyright: ©Copyright by Association
for Endocrine Oncology and Metabolism.
This is an Open Access article distributed
under the terms of the Creative Commons
Attribution Non-Commercial License
(http://creativecommons.org/licenses/
by-nc/4.0/) which permits unrestricted
non-commercial use, distribution, and
reproduction in any medium, provided the
original work is properly cited.
Funding: None.
Conflict of interest statement: The
authors declare that they have no
conflict of interest.
Data Availability Statement: All
relevant data are within the paper.
Bilateral adrenalectomy usually results in lifelong primary adrenal
insufficiency. Evidence exists that up to 34% of patients with Cushing’s
disease (CD) have some degree of endogenous cortisol secretion after
treatment; however, it is unusual that overt recurrence persists even after
the removal of the replacement therapy. We present a case of a patient
with an atypical corticotropinoma/carcinoma and CD recurrence after
bilateral adrenalectomy. A 59-year-old man presented with CD in 2010
and underwent a transsphenoidal adenomectomy. Pathohistological
evaluation suggested an 8 mm × 8 mm atypical corticotropinoma. CD
recurred 8 months after surgery. A total hypophysectomy was performed,
which led to complete remission, followed by recurrence 5 months later.
Subsequently, a bilateral two-stage adrenalectomy was performed
along with radiosurgical treatment. Postoperatively, the patient received
glucocorticoid replacement therapy. 2 years after the adrenalectomy, the
patient was diagnosed with Nelson’s syndrome. Fractionated radiotherapy
was given, and ACTH levels slightly decreased, but urinary free cortisol
(UFC) continued to increase. Glucocorticoid therapy was stopped, but UFC
increased to 1400 nmol/24 h (normal range 54-319 nmol/24 h) 3 years after
the adrenalectomy, accompanied by the recurrence of signs and symptoms
of CD. Abdominal computed tomography showed a 4 cm large mass in the
left adrenal bed suggestive of adrenal tissue, along with multiple liver lesions,
without signs of another primary tumor. The patient died 5 years after initial
diagnosis. This is the first case of recurrent CD after bilateral adrenalectomy.
This report highlights the importance of long-term patient monitoring after
total bilateral adrenalectomy and individual dosing of replacement therapy.
Key words: Recurrence; Cushing’s disease; pituitary carcinoma; bilateral
adrenalectomy; nelson’s syndrome

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Vičić et al.

1. Introduction cavernous sinus, accompanied with hyperpigmentation of

Bilateral adrenalectomy is used for patients with Cushing’s
disease (CD) who underwent a non-curative surgery or
as a life-preserving emergency treatment [1]. After the
procedure, patients with persistently increased ACTH
levels have been reported to regain detectable adrenal
function [2-7]. We present a case of a patient with atypical
corticotropinoma/carcinoma and the recurrence of CD
accompanied by clinical signs and symptoms after total
bilateral adrenalectomy.
2. Case Report
A 59-year-old man originally presented with CD in 2010.
Increased level of cortisol (serum cortisol 08:00h 1518
nmol/L (normal range 171-536 nmol/L), 17:00  h 1659
nmol/L (normal range 64-327)) with a loss of circadian
rhythm and increased level of ACTH (160.2 pmol/L,
normal range 1.6-13.9 pmol/L) were found. Urinary
free cortisol (UFC) was increased (2400 nmol/24  h,
normal range 54-319 nmol/24  h). Magnetic resonance
imaging (MRI) revealed intrasellar mass 8 mm × 8 mm
suggestive of a microadenoma. Transsphenoidal selective
adenomectomy was performed, and pathohistological
evaluation was suggestive of atypical corticotropinoma
(Ki-67 proliferation index of 7%, positive nuclear staining
for p53). Despite some improvement in clinical signs, the
patient had active CD (UFC 716 nmol/24 h). 8 months
after the initial surgery, UFC rose to 8923 nmol/24 h and
ACTH rose to 35.5 pmol/L (Figure 1).
the skin and increased ACTH level (125 pmol/L). Standard
fractionated radiotherapy was performed, after which
ACTH slightly decreased, but we observed continuous
increase in UFC levels while taking hydrocortisone
replacement. Replacement therapy was stopped, but
UFC increased to 1400 nmol/24 h (serum cortisol level
08:00h 643 nmol/L, 17:00 h 336 nmol/L), accompanied
by the recurrence of signs and symptoms of CD and
complete vision loss. MRI showed dramatic progression
of the pituitary tumor measuring 40 mm in the largest
diameter, invading both optical nerves and extending to
the frontal lobe (Figure 2a and b). Abdominal computed
tomography showed 40 mm × 5 mm large mass in the
left adrenal bed suggestive of adrenal tissue (Figure 2c),
along with the multiple liver lesions (Figure 2d). Tumor
markers were all within normal ranges, and besides
corticotropinoma, there were no signs of another primary
tumor. The patient died 5 years after the initial diagnosis
and his family refused an autopsy.
3. Discussion
Total bilateral adrenalectomy is considered to be a definitive
cure for CD [2], resulting in primary adrenal insufficiency
requiring lifelong glucocorticoid and mineralocorticoid
replacement therapy to prevent potentially fatal
Addisonian crisis [3]. It is not mandatory to routinely
measure UFC levels in patients taking hydrocortisone

MRI showed pituitary mass measuring 12  mm ×

10  mm × 8  mm invading the left cavernous sinus.
Total hypophysectomy led to complete remission, but
recurrence occurred only 5 months later. We performed
radiosurgical treatment of the remnant tumor mass, along
with bilateral two-stage adrenalectomy. Pathohistological
evaluation confirmed complete removal of the left
adrenal gland but was inconclusive in the case of the
right one. Postoperatively, the patient developed adrenal
insufficiency, which required long-term glucocorticoid
replacement therapy (hydrocortisone 20 + 10 mg daily).
Figure 1. Changes in patient’s ACTH and UFC after transsphenoidal
2  years after the adrenalectomy, the patient developed selective adenomectomy (a), total hypophysectomy (b), bilateral
Nelson’s syndrome. He presented with diplopia, due to two-stage adrenalectomy (c, d), and standard fractionated
15  mm × 9  mm pituitary tumor mass involving right radiotherapy (e)

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 Vičić et al.

a b

c d
Figure 2. Coronal (a) and sagittal (b) T1-weighted contrast enhanced magnetic resonance images showing pituitary tumor measuring
40 mm in the largest diameter, invading both optical nerves and extending to the frontal lobe. Abdominal computed tomography is showing
40 mm × 5 mm large mass in the left adrenal bed suggestive of adrenal tissue (c), along with the liver metastasis (d)

after the bilateral adrenalectomy, although long-term
follow-up of electrolytes and metabolic parameters is
recommended  [4]. However, endogenous cortisol
secretion has been described in up to 34% of the patients
after bilateral adrenalectomy. All of these patients needed
reduction of the hydrocortisone dose, but neither one
patient showed clinical signs of CD [5,6]. To the best of
our knowledge, this is the first case of a recurrent overt CD
after bilateral adrenalectomy, which persisted even after
the withdrawal of glucocorticoid replacement therapy.
Cortisol producing tissue has been described as adrenal
remnants after the procedure [5], or as an ectopic adrenal
tissue [7]. Some authors suggest the possibility of ACTH
driven hyperplasia of retained adrenal cortical cells [3] or
hyperplasia of adrenal rest tissue in the testes [8]. In our case,
an abdominal computerized tomography scan revealed a
mass in the left adrenal bed suggestive of adrenal tissue.
Pathohistological examination of the removed adrenal
glands confirmed a complete removal of the left adrenal
gland, which implies, in the absence of another ectopic
adrenal tissue, that the detected adrenal bed tissue formed
as a result of ACTH driven hyperplasia of retained cortical
cells. This report highlights the importance of long-term
surveillance for recurrent increased cortisol production
in patients after total bilateral adrenalectomy, especially
in patients with atypical corticotropinomas. It also advises
against routine administration of full replacement doses
and supports an individualized approach in determining
the maintenance dose in patients with detected cortisol
production.
Author Contributions
IV reviewed the previously published literature, wrote
the article and gave the final approval. MČ and JMR
participated in study design, acquisition of data, drafting the

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Vičić et al.
article, and gave the final approval. IK gave an idea for the
case study, participated in drafting the article and gave the
final approval. HIP performed radiological evaluation and
gave the final approval. VČ performed the surgery and was
engaged in patient’s follow-up, and gave the final approval.
LP performed pathohistological analyses and gave the final
approval. MV and GM were engaged in endocrinological
evaluations and follow-up and gave the final approval.
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