Abstract: Background Subclinical Cushing syndrome in patients with adrenal incidentalomas has been associated with an increased prevalence of the metabolic syndrome and car- diovascular risk. The management of these patients, be it conservative or surgical, is still debated, but there is accumulating evidence that surgery is best and that lapa- roscopic adrenalectomy, when possible, is the most pre- ferred procedure. Here we present the short- and long-term results of laparoscopic adrenalectomy for subclinical Cushing syndrome and determine the effect of this proce- dure on components of the metabolic syndrome. Methods Twenty-nine patients, 8 men and 21 women with adrenal incidentalomas and subclinical Cushing syn- drome who underwent laparoscopic adrenalectomy, were studied retrospectively. They had undergone postoperative follow-up for improvement or worsening of their arterial blood pressure, body weight, and fasting glucose level for a mean period of 77 months. Results: Preoperatively, 17 patients (58.6 %) had arterial hypertension, 14 (48.3%) had a body mass index exceeding 27 kg/m2, and 12 (41.4 %) had diabetes melli- tus. Postoperatively, a decrease in mean arterial pressure was found in 12 patients (70.6 %), a decrease in body mass index in 6 patients (42.9 %), and an improvement in gly- cemic control in 5 patients (41.7 %). Conclusions Laparoscopic adrenalectomy is beneficial in many patients with subclinical Cushing syndrome because it reduces arterial blood pressure, body weight, and fasting glucose levels. Prospective randomized studies are needed to compare laparoscopic adrenalectomy with a conserva- tive approach and to confirm these results.

1. Laparoscopic adrenalectomy in patients with subclinical
Cushing syndrome
Iraklis Perysinakis • Chrisanthi Marakaki • Spyridon Avlonitis •
Anastasia Katseli • Evangeline Vassilatou • Lambrini Papanastasiou •
George Piaditis • George N. Zografos
Received: 18 July 2012 / Accepted: 4 December 2012 / Published online: 26 January 2013
Ó Springer Science+Business Media New York 2013
Abstract
Background Subclinical Cushing syndrome in patients
with adrenal incidentalomas has been associated with an
increased prevalence of the metabolic syndrome and car-
diovascular risk. The management of these patients, be it
conservative or surgical, is still debated, but there is
accumulating evidence that surgery is best and that lapa-
roscopic adrenalectomy, when possible, is the most pre-
ferred procedure. Here we present the short- and long-term
results of laparoscopic adrenalectomy for subclinical
Cushing syndrome and determine the effect of this proce-
dure on components of the metabolic syndrome.
Methods Twenty-nine patients, 8 men and 21 women
with adrenal incidentalomas and subclinical Cushing syn-
drome who underwent laparoscopic adrenalectomy, were
studied retrospectively. They had undergone postoperative
follow-up for improvement or worsening of their arterial
blood pressure, body weight, and fasting glucose level for a
mean period of 77 months.
Results Preoperatively, 17 patients (58.6 %) had arterial
hypertension, 14 (48.3 %) had a body mass index
exceeding 27 kg/m2
, and 12 (41.4 %) had diabetes melli-
tus. Postoperatively, a decrease in mean arterial pressure
was found in 12 patients (70.6 %), a decrease in body mass
index in 6 patients (42.9 %), and an improvement in gly-
cemic control in 5 patients (41.7 %).
Conclusions Laparoscopic adrenalectomy is beneficial in
many patients with subclinical Cushing syndrome because
it reduces arterial blood pressure, body weight, and fasting
glucose levels. Prospective randomized studies are needed
to compare laparoscopic adrenalectomy with a conserva-
tive approach and to confirm these results.
Keywords Adenoma Á Autonomous cortisol secretion Á
Conservative treatment Á Laparoscopic adrenalectomy Á
Subclinical Cushing syndrome
Advances in diagnostic tools such as computed tomogra-
phy (CT) and magnetic resonance imaging over the last
few decades have resulted in the recognition of incidentally
discovered adrenal masses, initially described in autopsy
series, with an increasing frequency in every day clinical
practice [1]. The term adrenal incidentaloma (AI) is used
to describe an adrenal mass discovered by chance in the
process of performing an abdominal ultrasound or CT scan
for an unrelated extra-adrenal condition [2]. Most AIs are
nonsecretory, benign lesions. However, subclinical hor-
monal activity, mainly concerning glucocorticoid secre-
tion, is detected in a significant percentage of cases.
Approximately 5–20 % of these tumors present subclinical
cortisol hypersecretion, characterized by subtle alterations
of the hypothalamic–pituitary–adrenal (H–P–A) axis due to
adrenal autonomy, a disorder that has also been described
I. Perysinakis Á S. Avlonitis Á A. Katseli Á G. N. Zografos
3rd Department of Surgery, ‘‘George Gennimatas’’ General
Hospital of Athens, Athens, Greece
e-mail: iraklisper@gmail.com
C. Marakaki Á L. Papanastasiou Á G. Piaditis
Department of Endocrinology, ‘‘George Gennimatas’’ General
Hospital of Athens, Athens, Greece
E. Vassilatou
Endocrine Unit, 2nd Department of Internal Medicine, Attikon
University Hospital, Athens University Medical School,
Athens, Greece
G. N. Zografos (&)
10 K. Ourani street, 15237 Athens, Greece
e-mail: gnzografos@yahoo.com
123
Surg Endosc (2013) 27:2145–2148
DOI 10.1007/s00464-012-2730-5
and Other Interventional Techniques

2. as subclinical Cushing syndrome (SCS) because there is no
typical clinical phenotype [3–5]. Although these patients
lack many of the usual stigmata of overt Cushing syn-
drome, they may have diabetes mellitus (DM), hyperten-
sion, hyperlipidemia, osteoporosis, and obesity disorders
potentially attributable to autonomous glucocorticoid
secretion [3, 6]. Therapeutic choices in patients with AIs
and SCS are either close follow-up or surgery; however,
existing data are insufficient for guidance between the two
options [6]. Up till now, there are few studies comparing
conservative with surgical approach with conflicting results
[7, 8], while there is only one prospective randomized
study comparing conservative with laparoscopic surgical
management showing a more beneficial effect in the out-
come of operated patients [9].
In this study, we present the short- and long term results
of laparoscopic adrenalectomy (LA) for SCS regarding the
outcome of components of the metabolic syndrome in a
single surgical unit during the period 1997–2011.
Materials and methods
A cohort of 29 patients with AIs diagnosed with SCS
underwent LA in our surgical department from June 1997
to Aug 2011. The protocol for this study conformed to the
provisions of the Declaration of Helsinki.
Diagnosis of AI was based on detection of an adrenal
mass by abdominal CT scan performed for reasons not
related to H–P–A axis investigation. Exclusion criteria
from the study were: increased 24 h urine vanillylmandelic
acid, catecholamine, or metanephrine concentrations indi-
cating pheochromocytoma; increased aldosterone with
suppressed renin levels indicating hyperaldosteronism;
imaging features that led to suspicions of an adrenocortical
carcinoma; and signs and symptoms specific of cortisol
excess indicating overt Cushing syndrome.
The diagnosis of SCS was based on failure of cortisol to
be adequately suppressed after a post-low dose dexa-
methasone suppression test (dexamethasone 0.5 mg orally
every 6 h for 48 h, plasma cortisol level C 1.8 lg/dl)
combined with an abnormal result of at least one other test
of the H–P–A axis such as blunted diurnal cortisol circa-
dian rhythm (plasma cortisol at 24.00/8.00 percent
ratio [ 50 %), suppressed adrenocorticotropic hormone
(ACTH) concentrations (morning plasma ACTH 10 pg/
ml), and elevated 24-h urinary free cortisol excretion (24-h
urinary free cortisol [ 100 mg) in the absence of clinical
signs of cortisol excess [10, 11].
All hormone assays were performed with commercially
available kits. Plasma (or serum) cortisol was measured by
electrochemiluminescence immunoassay (Elecsys, Roche
Diagnostics, Manheim, Germany) with a reported
functional sensitivity of 2.0 nmol/l, lower detection limit of
0.5 nmol/l, and intra- and interassay coefficients of varia-
tion 1.3 and 1.6 %, respectively. Urinary free cortisol was
measured after dichloromethane extraction with the same
assay. Plasma ACTH was measured by immunoradiometric
assay (Nichols Institute Diagnostics, San Juan Capistrano,
CA, USA) with lower detection limit of 0.22 pmol/l and
intra- and interassay coefficients of variation 5 and 6 %,
respectively. Hematological profile, lipid profile, serum
electrolytes, glucose, creatinine, and liver function tests
were determined by routine laboratory methods. All
patients received oral hydrocortisone postoperatively
(10–5–5 mg) for 30 days. If recovery of the H–P–A axis
was documented, hydrocortisone was discontinued.
Between June 1997 and August 2011, a total of 240
patients with 251 adrenal masses were surgically treated.
The subgroup of SCS consisted of 29 patients, eight men
and 21 women, with a mean age of 54 years, ranging from
31 to 68 years. Eighteen patients underwent left adrenal-
ectomy and 11 patients underwent right adrenalectomy. All
procedures in the SCS subgroup were completed by lapa-
roscopy. In three patients, histological diagnosis was nod-
ular hyperplasia, while the rest were adrenocortical
adenomas. Mean tumor size was 3.7 cm, ranging from 1.9
to 6.7 cm. One woman with left adrenalectomy established
a low-output external pancreatic fistula, which was treated
conservatively. Mean postoperative hospital stay was
2.2 days. Patients were followed up for a mean period of
77 months.
All subjects underwent clinical examination preopera-
tively and postoperatively at 6 and 12 months, recording
the presence of arterial hypertension, obesity, dyslipide-
mia, and type 2 DM. Arterial hypertension was defined as
values of systolic blood pressure C 135 mmHg and/or
diastolic blood pressure of C85 mmHg or whether patients
were receiving antihypertensive treatment. Obesity was
considered when patients’ body mass index (BMI) was
greater than 30 kg/m2
. DM was diagnosed World Health
Organization criteria (glucose levels greater than 126 mg/
dl) or whether patients were receiving hypoglycemic
treatment.
Patients’ data were retrospectively analyzed in order to
assess the impact of the operation on hypertension, dia-
betes, and BMI. The LA was performed by a skilled sur-
gical team via the lateral transperitoneal approach.
The transperitoneal lateral decubitus approach was
chosen because it was considered the best for maximal
exposure of the gland and adjacent organs and vessels. For
adrenal masses in the right side, three 10-mm trocars and
one 5-mm trocar were used. For adrenal masses in the left
side, two 10-mm trocars and two 5-mm trocars were used.
Pneumoperitoneum with Hasson technique was performed
to avoid any relevant morbidity.
2146 Surg Endosc (2013) 27:2145–2148
123

3. The specimen was placed in a bag and extracted through
an extension of the incision made for the Hasson technique.
The length of the extension depends on the tumor size, and
the tumor must be removed from the abdomen carefully to
ensure it is intact for histologic examination.
Results
All 29 adrenalectomies were successfully completed lapa-
roscopically. One woman with an adrenal mass established
a low-output pancreatic fistula, which was treated conser-
vatively. No operative mortality occurred.
Body weight, blood pressure, and fasting glucose levels
were compared between baselines, 6 and 12 months and the
end of follow-up.
In this series, 17 patients (58.6 %) had arterial hyper-
tension, 12 patients (41.4 %) had DM, and 14 patients
(48.3 %) had a preoperative BMI exceeding 27 kg/m2
[2].
Postoperatively, a decrease in mean arterial pressure was
shown in 12 of 17 patients (70.6 %), which led to a
reduction in the dosage or the number of antihypertensive
drugs provided, or even elimination of the need for medi-
cation in two patients. Five patients (41.7 %), with pre-
operatively impaired glucose tolerance or diabetes, became
euglycemic after surgery. BMI was reduced in six patients
(42.9 %) postoperatively.
In two patients, hydrocortisone was discontinued
6 months after the operation. There were no patients in this
series receiving hydrocortisone more than 6 months after
the operation.
Discussion
Our study suggests that LA in patients with SCS is asso-
ciated with improving body weight, fasting glucose levels,
and arterial blood pressure, thus providing benefits in terms
of cardiovascular risk, but its effects on long-term outcome
and quality of life are unknown.
The clinical relevance of SCS is still conflicting, and
most importantly, the benefits of surgical treatment remain
controversial, although an improvement of metabolic status
is suggested in patients after the removal of adrenal mass.
SCS is defined as mild cortisol hypersecretion detected
biochemically without the typical clinical phenotype of
Cushing syndrome. There is a lack of consensus on the best
diagnostic criteria for the evaluation of SCS in patients
with AIs. In the largest study of patients with AI, a com-
bination of a positive 1-mg dexamethasone suppression test
and low ACTH was the most common biochemical
abnormality in patients with SCS [11]. Autonomous cor-
tisol secretion is the most frequent (5–20 %) hormonal
abnormality in patients with AIs [4]. The Italian Study
Group on Adrenal Tumors documented a prevalence of
SCS of 9.2 % among patients with AIs [11]. Subclinical
autonomous cortisol hypersecretion may be intermittent in
a significant percentage of patients, while patients develop
rarely overt disease [5]. Patients with SCS are more likely
to have hypertension, dyslipidemia, impaired glucose tol-
erance or type 2 DM, and evidence of atherosclerosis
compared to normal subjects, thus presenting a different
cardiovascular risk profile [6, 12]. The management of SCS
aims at improving the aforementioned entities, which are
potentially related to autonomous glucocorticoid hyperse-
cretion, thus theoretically resulting in cardiovascular pre-
vention [13].
The choice between close follow-up and surgical treat-
ment of SCS is still a debated issue in the literature. In the
absence of a prospective randomized study, it seems rea-
sonable to consider for surgery younger patients with SCS
who display diseases potentially attributable to excessive
cortisol (hypertension, diabetes, abdominal obesity, and
osteoporosis) that are of recent onset, are resistant to
optimal conservative management, or are rapidly worsen-
ing [2, 5, 14].
To date, LA is the gold standard for the management
of SCS because it is a safe, effective, and less expensive
procedure than open adrenalectomy [15–20]. Compared
with the traditional open resection, LA is associated with
less postoperative pain, shorter hospital stay and recovery
time, and better patient satisfaction rates. These clear
advantages of LA did not encourage any prospective
randomized, controlled trials comparing the new tech-
nique with the classical open (either transabdominal or
retroperitoneal) technique [20]. Concomitant conditions
such as morbid obesity, bleeding disorders, or previous
abdominal procedures are considered to be relevant con-
traindications, depending on the laparoscopic experience
of the surgeon.
Several authors have found the endoscopic retroperito-
neal approach to be as equally effective and safe for
excising small adrenal lesions [21]. LA for benign tumors
has minimal morbidity and mortality, a fact clearly shown
in the present study. As far as age is concerned, Reincke
et al. suggest adrenalectomy in patients younger than
50 years [22], while Terzolo et al. [23] suggested it in even
younger patients (younger than 40 years).
Although LA was not compared to medical treatment in
this study, our results are in accordance with those of
several studies in literature. Recent studies have confirmed
better management of SCS by LA, emphasizing the
improvement of several components of metabolic syn-
drome and the decrease in cardiovascular risk [8, 9, 24].
However, a large prospective randomized study is still
needed to confirm the above mentioned results and
Surg Endosc (2013) 27:2145–2148 2147
123

4. establish the best diagnostic approach to identify patients
with SCS who may benefit from surgery.
Disclosures Drs. Perysinakis, Marakaki, Avlonitis, Katseli, Vassilatou,
Papanastasiou, Piaditis, and Zografos have no conflicts of interest or
financial ties to disclose.
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