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Prophylactic Adrenalectomy
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
MehmetHaciyanli , EmineOzlemGur ,
andSeldaGucekHaciyanli
21
21.1 Introduction
Over the past decades, widespread use of
screening, genetic testing and innovations in
surgical techniques have resulted in early diagnosis and identication of high risk patients for
cancer development and hence resulted in
improved overall survival and clinical outcomes across many cancer types. As a consequence, “Prophylactic Surgery” concept
emerged. Prophylactic surgery or preventive
surgery is dened as “surgery to remove an
organ gland that shows no signs of cancer, in an
attempt to prevent development of cancer of
that organ or gland” in National Cancer Institute
(NCI) Dictionary of Cancer Term [1].
To apply a prophylactic surgery to an organ or
gland, the balance between the oncological benet and quality of life versus the risk of operation
and cost efciency should be considered.
Prophylactic thyroidectomy for gene carriers of
Multiple Endocrine Neoplasia (MEN) type 2
M. Haciyanli · E. O. Gur (*)
Faculty of Medicine, Department of Surgery,
Division of General Surgery, Izmir Katip Celebi
University, Izmir, Turkey
e-mail: mehmet.haciyanli@ikc.edu.tr;
emineozlem.gur@ikc.edu.tr
S. G. Haciyanli
Izmir Katip Celebi University, Ataturk Training and
Research Hospital, General Surgery Clinic,
Izmir, Turkey
e-mail: s.gucekhaciyanli@saglik.gov.tr
(before medullary thyroid cancer (MTC) develop)
has been well-dened example of prophylactic
surgery in endocrine surgery eld. However, the
data about the indications of the prophylactic surgery of the adrenal glands is very limited in the
literature. Moreover, currently there is no place
for “prophylactic adrenalectomy” similar to that
of “prophylactic thyroidectomy” in classical
manner. When the term “prophylactic adrenalectomy” is searched in PubMed, only few anecdotal
reports can be found. The reason is that for most
hereditary syndromes causing adrenal tumors,
surgeons wait for lesions to develop before to
resect the adrenal because the risk is not worth
the benet, also delay will not cause same issue
as in MTC.The existence of two adrenal glands
and absence of ideal substitute for adrenal hormones also increases the complexity of the issue.
Adrenalectomy for large adrenal tumors that
have high risk for cancer is not considered “prophylactic”; it is considered “diagnostic” and possibly “therapeutic” if it turns out to be a cancer.
However, in the area of endocrine disease,
especially in adrenal disease, risk reduction surgery can be used to prevent the development of
severe conditions. Instead of total adrenalectomy,
function-preserving, cortical sparing adrenalectomies (CSA) have been used in certain circumstances, especially in some hereditary bilateral
pheochromocytomas (PCC) to “prevent” adrenal
insufciency which is a debilitating condition,
require lifelong steroid replacement and are associated with long-term morbidity and even death.
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021
O. N. Dilek et al. (eds.), Prophylactic Surgery, https://doi.org/10.1007/978-3-030-66853-2_21
227
228
M. Haciyanli et al.
So CSA can be a non-classical example of preventive surgery (which prevents functional loss
while treating the tumor) which has been increasingly performed in PCC patients with mutations
of RET or Von Hippel Lindau (VHL), because of
the low risk of malignancy (<5%) and high risk
of bilaterality (50%) [2, 3].
Another two examples for preventive adrenalectomy might be the surgery for patients with
adrenal incidentalomas (AI) and autonomous
cortisol secretion (ACS). Patients with ACS have
an increasing risk of developing severe cortisolrelated comorbidities such as atherosclerosis,
hypertension, diabetes, cardiovascular events and
related mortality, bone fractures, and infectious
diseases. Considering the increasing number of
patients with this condition, it is important to
identify high risk patients to perform adrenalectomy to prevent those complications.
Under the highlights of the current literature,
we will discuss the current status of preventive
and diagnostic surgery for adrenal lesions.
21.2 History
When “prophylactic” or “preventive” “adrenalectomy” terms are used as a search term in PubMed,
only few anecdotal reports were encountered.
Prophylactic bilateral adrenalectomy (± oophorectomy) was used to control the disease in
patients having advanced breast cancer in 1960s
[4, 5]. However with the advances in medical
treatment with pharmaceuticals and the inadvertent results of such a surgery, it has not been used
anymore for such an indication.
A group of researchers proposed prophylactic
bilateral adrenalectomy as an option for patients
affected by Congenital Adrenal Hyperplasia
(CAH) and performed the operation in a few
patients having a double null mutation of the
CYP21 gene as a part of an approved research
protocol [6, 7]. They concluded that prophylactic
adrenalectomy in young children with such mutations should remain experimental [7].
Up to 40% of patients with PCC have diseasespecic germline mutations and the disease is
hereditary. Of 60% of the remaining sporadic
patients, at least 1/3 have somatic mutation in
predisposing genes [8].
MEN 2, VHL syndrome, Neurobromatosis
Type 1 (NF-1) (=von Recklinghausen’s Disease—
VRD) are well-known examples of genetic syndromes associated with PCC.
With the advances in genetic analysis, the carriers can be easily identied and prophylactic
thyroidectomy concept has been a wellestablished approach for MEN2 to prevent the
development of medullary thyroid cancer which
is an aggressive disease. However, prophylactic
adrenalectomy concept has never been well
established for those carriers before the development of one-sided disease. Since PCC is bilateral
almost in 50% of the patients with MEN2 and
VHL, some suggested total bilateral adrenalectomy in those patients including the patients with
unilateral PCC to reduce the risk of recurrence
and eliminate the risk of malignancy in the future.
But it has been detected that malignancy is
uncommon in both VHL and MEN2, and the
complications of bilateral total adrenalectomy
are disastrous, patients need lifelong steroid and
hospital dependence. To avoid from such severe
complications, there has been an increasing trend
to preserve adrenal tissue in patients with MEN
2, VHL, and NF-1. CSA can be classied as a
preventive surgery which prevents the lifelong
intrinsic steroid insufciency.
21.3 PCC-Heritable PCC
PCCs are rare endocrine tumors originating from
chromafn cells in the adrenal medulla and
secrete excess catecholamines such as epinephrine, norepinephrine, dopamine and/or their
metabolites including metanephrine, normetanephrine, and 3-methoxytyramine, respectively
[9, 10]. The annual incidence of PCCs in the
United States is estimated about 500–1600 cases
per year and the prevalence of them is estimated
to be 1–2500 and 1–6500 [11]. The patients are
typically symptomatic in their fourth or fth
decade of life, with an equal sex distribution [12].
The classical presentation of the disease consists of episodic ushing, diaphoresis, headaches,
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and hypertension, in approximately 40% of
patients [13]. Almost 10% of patients have bilateral tumors [14]. PCCs comprise about 4–8% of
all adrenal incidentalomas, and about 21.1–
57.6% of all PCCs are discovered incidentally on
imaging [15, 16]. About 10% of all PCCs are
malignant, but the likelihood of malignancy
depends on the presence of certain germline
mutations (SDHB in particular) [17, 18].
The contribution of genetic predisposition
either from a familial predisposition or de novo
mutation [8, 19] increased to 40% with the discovery of new susceptibility genes. Patients suspected to have PCC should rst undergo
biochemical testing of catecholamines and their
metabolites to establish or rule out the diagnosis.
After the biochemical diagnosis has been reached,
genetic testing must be completed. Then anatomical and functional imaging should be performed,
before surgery. The extent of adrenalectomy and
type of surgery is individualized based on multiple factors such as the results of genetic testing,
the size and bilaterality of the tumor, the likelihood of malignancy, body mass index of the
patients, and the experience of the surgeon.
21.3.1 Biochemical Studies
The biochemical diagnosis of PCCs depends on
the measurement of catecholamines and their
metabolites (metanephrine and normetanephrine) both in serum and urine. The metabolites
are superior in diagnosis to circulating catecholamines [20]. The most accurate biomarker for
diagnosis is a plasma free metanephrine (a sensitivity of 94%, specicity of 93%) [21]. Endocrine
Society Practice Guidelines recommended for
the initial workup for PCC either plasma free or
24-h urinary fractionated metanephrines [22].
False-positive results may be due to a drug
interference (tricyclic antidepressants, acetaminophen, sulfasalazine, phenoxybenzamine,
sotalol, labetalol, alpha-methyldopa, monoamine oxidase inhibitors, sympathomimetics,
buspirone, cocaine, and levodopa) or laboratory
errors [9, 23]. Repeat testing is recommended
after the cessation of medications.
21.3.2 Genetic Background
Since up to 40% of PCCs may have genetic predisposition, all patients with a diagnosis of PCC
should be referred for genetic testing [24, 25].
The mutations determine the pathophysiology
and biologic behavior of PCC and the management of those patient and their affected members
of family are dictated by those inherited mutations. More than 20 gene mutations have been
detected in patients with PCC and paraganglioma
(PGL) which lead tumor development as either a
germline (inherited) or somatic mutation (noninherited) [8, 26, 27].
Patients with PCC and PGL with these mutations can be divided into three groups according
to the cancer genome map (Table21.1) [28].
PCC and PGL related to mutations in SDHx
subunits are often multiple, aggressive and metastatic tumors compared to those originating from
other mutations, especially cluster 2 mutations
[29]. More specically, SDHB mutation has
increased risk of malignancy [30].
About 95–100% of patients with VHL syndrome are related to the mutation in the VHL
tumor suppressor gene. The tumors with mutations in cluster 1 have a noradrenergic biochemical
phenotype. They produce norepinephrine and
dopamine, not epinephrine [31].
Table 21.1 Genetic mutations in PCC and PGL according to cancer genome
Cluster 3
Cluster 1
Pseudohypoxic Krebs
cycle-related genes
SDHx
SDHA, SDHB,
SDHC, SDHD
SDHAF2
FH
MDH2
IDH1
VHL/EPAS1
VHL
PHD1
(EGLN1/2)
HIF2A/EPAS1/2
Cluster 2
Kinase signalingrelated genes
RET Somatic
NF 1
HRAS
TMEM127
MAX
Wnt
Signalingrelated genes
230
M. Haciyanli et al.
The most common hereditary syndrome in
patients with cluster 2 mutations is MEN2 and
the majority adrenergic biochemical phenotype
(excess epinephrine production). Norepinephrine
may increase or at normal levels in them [31].
Most PCCs associated with those mutations are
benign but have a high rate of multifocality [32].
Those tumors with cluster 3 type mutations
are related to aggressive features [28].
The germline mutation and biochemical phenotype of this category is unknown [31–33].
In general, the risk of metastatic disease in
decreasing order is as follows: mutations associated
with cluster 1 mutations, cluster 3, cluster 2 [29].
21.4 Genetic Syndromes
Associated withPCC
ANDPGL
21.4.1 MEN 2 Syndrome
MEN2 syndromes are autosomal dominant diseases and caused by mutations in the RET protooncogene. Medullary thyroid cancer develops in
almost 100% of patients with MEN2 (A and B),
whereas PCC in 50% of patients with MEN2
(both in A and in B) [34].
In MEN syndromes, the tumor is often localized in the adrenal medulla and paraganglioma
(PGL) is very rare [29]. PCCs in this syndrome
make up 5% of all PCCs [35]. Bilateral adrenal
involvement occurs in 50–60% [2, 35]. It can be
synchronous or metachronous. Its biochemical
phenotype is adrenergic [36].
Metastatic disease is quite rare (≤1%) [9].
Hyperparathyroidism is another component of
MEN2A syndrome, whereas neuromas and marfanoid habits can be seen in patients with
MEN2B.PCC should be treated prior to surgery
for other components of the syndrome.
cysts, renal carcinoma of clear cell type, pancreatic neuroendocrine tumors, cysts and cystadenomas, PPGLs, cystadenomas in gonads, benign
asymptomatic lung and liver lesions can be seen
in this syndrome [2].
PCC and rarely PGLs are seen in about 20%
of patients with a young age of onset. Tumors are
usually of adrenal origin and produce norepinephrine. Twenty percent of PCCs in this syndrome are bilateral [37, 38] and metastatic
disease is rare [5%].
21.4.3 NF1 Syndrome
NF1 is an autosomal dominant disease caused by
mutation in the NF1 gene and characterized by
multiple neuromas and peripheral nerve sheath
malignant tumors (15%) [39]. In addition, café au
lait spots, freckles in the axilla and inguinal areas,
malignant glioma, bone lesions, gastrointestinal
stromal tumors, and PCC may occur [40, 41].
PCC develops in 1–5% of patients with NF-1
[22]. They constitute 1% of all patients with PCC
[40]. All patients with PCC and NF1 exhibit cuta-
neous manifestations on physical examination.
Tumors are bilateral in 20% of cases [42].
Approximately 7–12% of them are metastatic [22].
21.4.4 Hereditary PGL Syndromes
Type 1–5 (SDH Complex)
The PGL syndrome arises from mutations on
genes encoding the enzyme succinate dehydrogenase (SDH) with autosomal dominant inheritance. These syndromes are more often
associated with PGL.Head and neck PGLs are
common. PCCs are seen rarely. Malignancy rate
is higher in SDHB mutations and 30–70% malignancy has been reported; in other types, malignancy rate is low [22].
21.4.2 VHL Syndrome
VHL Syndrome is an autosomal dominant disease caused by the germline mutation in the VHL
tumor suppressor gene. Cerebellar and spinal
hemangioblastomas, retinal hemangioma, renal
21.5 Genetic Testing
All current guidelines worldwide recommend the
genetic testing to all patients having PCC and PGL
[9, 24, 43] regardless of family history or age.
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Next generation sequencing (NGS) is currently the gold standard for genetic testing. A
consensus statement on NGS testing for patients
with inherited PCC explains the variety of associated genes and standardizes reporting [44]. With
NGS, it can be possible to test the most common
predisposing genes (SDHA, SDHAF2, SDHB,
SDHC, SDHD, TMEM127, VHL EGLN1, FH,
KIF1B, MAX, MEN1, NF1, and RET) accurately. The genes typically are sequenced and
evaluated for duplications and deletions of exon.
Due to the complexity of interpreting the results,
the patients should be offered to have a genetic
consultation before testing.
Genetic testing enables the surgeon to individualize surgical approaches and decide the extent of
adrenalectomy. Patients with an SDHB mutation
which typically represents more aggressive disease were more likely to be operated via an open
surgery and total adrenalectomy even in bilateral
cases [45]. On the other hand, approximately 50%
of MEN2 and 20% of VHL patients have bilateral
PCC and since the metastatic diseases are quite
low in those patients identied genetically, cortical
sparing adrenalectomy (CSA) which will be discussed further in this chapter should be considered
to prevent adrenal insufciency.
21.6 Imaging
After biochemical conrmation of PCC, imaging
of tumor with either computed tomography (CT)
and/or magnetic resonance imaging (MRI) is
essential for surgical planning. Both of those
techniques have similar high sensitivity and specicity (90–100 and 70–80% respectively) for
identifying adrenal tumors [
9].
PCC will measure more than ten Hounseld
on non-contrasted CT images and have marked
enhancement on arterial phase images as well as
delayed venous washout on contrasted CT images
[46, 47]. Cystic changes, intratumoral hemorrhage, central necrosis, and internal calcications
may be detected as the lesion increases in size
(Fig. 21.1). MRI shows T2 enhancement with
contrast (light bulb sign). The adrenal mass may
also appear heterogenous due to central necrosis,
cystic changes, or hemorrhage [
47] (Fig.21.2).
Bilateral lesions on CT/MRI must raise suspicion for a hereditary disease. Functional imaging
can be used in such a situation or when a metastatic disease is suspected. Functional imaging
methods, which use radiotracers dependent on
glucose metabolism, catecholamine secretion
and metabolism, or tumor somatostatin receptor
existence aid in the detection of additional
smaller, functioning lesions in the same or contralateral gland which is critical for decision on
the extent of the surgery. So functional imaging
should be performed before decision on cortical
sparing adrenalectomy in hereditary or bilateral
PCC.
123I-metaiodobenzylguanidine (MIBG) is an
effective functional imaging method with a sensitivity of around 90% and specicity of 70–100%
for isolated PCC [48, 49]. However, its sensitivity decreases with extra-adrenal, metastatic, and
Fig. 21.1 The hypodense solid mass in right adrenal gland in portal venous phase axial and coronal computed
tomography images
232
Fig. 21.2 Right adrenal mass in MRI images. OP out of phase, IP in phase, FS T2 fat sat T2, PV portal venous phase
M. Haciyanli et al.
recurrent PCCs [48–50]. It may be useful in
highly selected cases such as for patients with
negative genetic screens and those with bilateral
adrenal tumors, both of which have suspicious
features for PCC based on CT/MRI ndings.
Positron emission tomography (PET)/CT
using 18F-uordeoxyglucose (18F-FDG), an
18F-3,4-dihydroxyphenylalanine (18F-DOPA)
has been evaluated in patients with PCC but
found that 18F-FDA was superior to 18F-DOPA
and 123I-MIBG in localizing metastatic disease [50]. However, 18F-FDA is available only
at the United States. 18F-FDG PET/CT has a
high sensitivity for SDHx and VHL-related
PCC, but 18F-DOPA PET/CT has higher performance in sporadic as well as in MEN2 and
NF1-related PCC and is the more appropriate
functional imaging choice for those patients
[50, 51].
PCCs express somatostatin receptors like
many other neuroendocrine tumors. There is an
increasing report demonstrating the superiority
of (68Ga)-DOTATATE PET/CT in the detection
of PCC compared with other functional imaging
methods [52]. (68Ga)-DOTATATE PET/CT may
become the primary functional imaging method
for PCCs when indicated [22].
21.6.1 Diagnosis ofHereditary PCC
PCC is detected during the genetic diagnosis or
during the follow-up of mutation carriers who are
diagnosed by familial screening. The steps of
diagnosis in hereditary cases are identical those
of sporadic cases, but the option of CSA is more
obvious in mutation carriers because the PCC is
generally smaller.
When PCC is present at the genetic diagnosis
after the biochemical diagnosis of PCC, conventional imaging (CT/MRI) is performed to
determine the size of the PCC, the number of
lesions, and the possibility of performing a
CSA.The functional imaging with 18F-FDOPA
or (68Ga)-DOTATATE PET/CT is important in
hereditary PCC for the decision process for CSA
[22, 53].
In mutation carriers (no PCC at the time of
genetic diagnosis), there is no consensus on the
diagnosis of PCC in those patients but the follow up is necessary for the option of CSA.
Symptoms and signs of catecholamine oversecretion are usually absent in mutation carriers but
metanephrines may increase progressively in
time. Monitorization of normetanephrines and
metanephrines both in plasma and urine annually
21 Prophylactic Adrenalectomy
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should be done annually throughout the patient’s
lifetime.
The role of imaging during the follow-up of
those patients is not known. The imaging before
biochemical diagnosis may aid in the detection of
a small and non-secreting PCC [54]. This screening would help in decision for an early surgery
and CSA. The use of MRI rather than CT in
childhood may be considered to avoid radiation
exposure. Some suggest adrenal MRI every
3–5years and there is likely no place for functional imaging in this setting of surveillance [54].
21.7 Preoperative Considerations
The presurgical management of partial adrenalectomy does not differ than the classical adrenalectomy for PCC. The Endocrine Society
guidelines recommend preoperative use of
α-blockers followed by β-blockers for the maintenance of normal blood pressure levels [9].
Some have reported successful results with preoperative use of calcium channel blockers, but
the major factor in the treatment is the experience
of the surgeon and anesthesiologist in the management of PCC [53].
21.7.1 Candidates forCSA
The patients at risk for adrenal insufciency are
those necessitating synchronous or metachronous bilateral adrenalectomy. The ideal candidates are patients with hereditary PCC with VHL,
MEN2, and NF-1 syndromes, and with small
tumors on the remaining adrenal who had a previous contralateral total adrenalectomy.
Patients having synchronous or metachronous
sporadic bilateral PCCs may be another group of
candidates. Another group of patients candidate
for CSA are those with a single gland, i.e., patients
who had one of their adrenal glands resected due
to trauma or renal surgery. Partial adrenalectomy
has been performed for some patients having
Conn’s disease and adrenal Cushing disease but
those two are out of context of this chapter.
21.7.2 CSA Technical Points
andResults
The three questions related with CSA to be
answered are:
1. Does it have a very low risk of malignancy?
2. Does it have an acceptable risk of
recurrence?
3. Does it maintain normal adrenal cortical
function?
The rst modern clinical use of partial adrenalectomy (open, bilateral) was reported by van
Heerden etal. (1985) from Mayo Clinic for the
treatment of bilateral PCCs in a pilot patient with
MEN 2A syndrome [55].The rst transabdominal laparoscopic adrenalectomy was performed
in 1992 [56]. Laparoscopic retroperitoneal adrenalectomy was described by Mercan etal. (1995)
and proposed as a good alternative in selected
cases [57, 58]. In 1996, laparoscopic partial adrenalectomy method was reported by Walsz [59].
Surgical techniques for adrenalectomy include
both open and minimally invasive (laparoscopic
or robotic) approaches. When operating a patient
with PCC, early ligation of the adrenal vein, and
minimal manipulation of the tumor to prevent
release of catecholamines and tumor rupture are
the key principals. Minimally invasive adrenalectomy is the preferred operation for PCCs via with
either the laparascopic transabdominal adrenalectomy (TA) or posterior retroperitoneoscopic
adrenalectomy (PRA) [60–62] which depends on
surgeon’s experiences, as well as factors such as
patients’ body mass index, anatomy, tumor characteristics (size and location), and history of prior
abdominal or retroperitoneal procedures.
Both approaches have different advantages:
TA approach can be used in larger tumors (>6cm)
since the working space is satisfactory and it is
easy to convert to open if necessary. It can be performed in patients with prior upper abdominal
surgery but adhesions may be problematic. On
the other hand, the PRA approach provides direct
access to the adrenal gland, without the need for
mobilization or adhesiolysis. Another advantage
234
M. Haciyanli et al.
of PRA is the ability to perform bilateral adrenalectomy without repositioning the patient.
Robotic adrenalectomy, using both TA and
PRA approaches, has been described for PCC
[63, 64] having advantages on surgeons
perspective.
Open transabdominal adrenalectomy is chosen for patients having suspiciously malignant/
invasive PCC or having large tumors at risk for
rupture. Furthermore, open adrenalectomy
should be considered in patients with SDHB,
TMEM127, or FH germline mutations, since
these mutations are associated with a higher risk
of malignancy and recurrence compared with
germline mutations in NF1, RET, or VHL [65].
Preserving the healthy cortical tissue by
means of partial adrenalectomy has evolved to
maintain the adrenal cortical functions and to
keep patients away from the adrenal insufciency. Many different nomenclatures have been
used for the approach such as “partial,” “subtotal,” “adrenal−/organ−/cortical-preserving,” and
“adrenal−/organ−/cortical-sparing” adrenalectomy. However, intraoperative discrimination
between the medulla and the cortex is impossible
intraoperatively.
The volume of residual adrenal tissue needed
to preserve a functioning gland is one of the challenging issue in partial adrenalectomy.
Preservation of at least 15–30% of adrenal tissue
during bilateral subtotal adrenalectomy is necessary for normal function [66]. The remaining
adrenal tissue must be more than 30% of the
gland if only one side adrenal gland left in situ
[67]. Although PCC must have a low risk for
malignancy, the tumor should be resected with a
rim of healthy cortical tissue (3mm), instead of
enucleation [68]. The guideline by The Society of
American Gastrointestinal and Endoscopic
Surgeons (SAGES) recommended the intraoperative laparoscopic ultrasound in partial adrenalectomy to ensure a clear distinction between
tumor and normal tissue [69]. The use of indocyanine green (ICG) uorescence imaging in
partial adrenalectomy is helpful in guiding the
extent of resection for the conrmation of remnant viability [70].
Ligation of adrenal vein in CSA is another
controversial point. Currently several comparative studies suggested that no difference has been
observed in steroid dependence between patients
with preserved or ligated adrenal vein [71, 72].
Another issue is the preservation of arterial blood
supply to the gland. The mobilization of the gland
to be preserved from retroperitoneum has not
been recommended in order to ensure adequate
blood supply [73].
The outcomes of partial adrenalectomies are
confusing in the literature. Patients with MEN 2
who undergo CSA have a 3% risk of ipsilateral
recurrence compared to 2% of total adrenalectomy at 10years. The rate of steroid dependency
has been reported up to 43% [37]. However, the
results of CSA for patients with VHL is encouraging: Benhammou etal. (2010) reported 11% of
patients developed recurrence within the ipsilateral adrenal gland remnant and 11% of patients
developed a recurrent PCC within the contralateral adrenal gland requiring a partial adrenalectomy and only 11% of patients became steroid
dependent and no patients developed metastatic
disease [74].
Currently, the indications for CSA are increasing and patients with bilateral benign familial
PCCs with VHL, MEN2, and NF-1 syndrome
seem to be ideal candidates. This approach has
been demonstrated to prevent postoperative adrenal insufciency in up to 90% of patients [53,
68], although the exact amount of remnant adre-
nal gland required is unknown.
21.8 Autonomic Cortisol
Hypersecretion (Subclinical
Cushing’s Syndrome)
Autonomous cortisol secretion (ACS) without
specic signs and symptoms of Cushing’s syndrome is termed subclinical Cushing’s syndrome
(SCS). Increasing use of abdominal imaging
modalities for various reasons has also led to the
increasing detection of adrenal incidentalomas
(AI) and biochemical evaluation of those patients
revealed hypercortisolism.
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Different terminology for the phenomenon
has been used including “Subclinical Cushing’s
syndrome,” “Subclinical Hypercortisolism,” and
“Subclinical Autonomous Glucocorticoid
Hypersecretion,” “Dysregulated hypercortisolism,” and “Preclinical Cushing’s Syndrome.”
We are going to use ACS in our chapter.
ACS appeared as the most common functional
abnormality in AI patients. Almost 5–20% of
adrenal incidentalomas exhibit autonomous cortisol hypersecretion (ACS) subclinically [75].
The optimal management of patients with ACS
has not been claried yet. It is known that signicant comorbidities are associated with ACS, and
some improvement in associated comorbidities
after adrenalectomy have been reported [76, 77].
So we discuss the surgery for ACS in the context
of “prophylactic adrenalectomy” which may
have a role to prevent the development of
hypercortisolism- associated comorbidities.
21.9 Components ofACS
The secondary screening tests that were recommended to show excess cortisol secretion are
late-night salivary cortisol (LNSC) and urinary
free cortisol (UFC) [
tic test for Cushing’s syndrome. LNSC is an easier test for the patients because they can collect
the samples at home. On the other hand, LNSC
test results can be dependent to the patients’
sleeping rhythm at the night for the Cushing’s
syndrome. LNSC has a conjunction with low
dose DST for the ACS diagnosis. The sensitivity
and specicity of LNSC test for ACS are more
than 80% if it has been used with low dose DST
85]. UFC is also effected by a lot of parameters
[
such as chronic anxiety, depression, obesity, and
high uid intake [86]. As with LNSC, a normal
UFC does not exclude ACS [87].
The imaging ndings are discussed in detail
under the heading of incidentaloma in this
chapter.
83, 84]. LNSC is a diagnos-
21.10.1 Clinical Presentation
1. Abdominal imaging revealing an adrenal mass
2. Hypercortisolism on biochemical evaluation
3. No classic clinical signs of overt Cushing’s
syndrome [78]
21.10 Diagnosis
The rst screening biochemical test is 1mg (low
dose) overnight dexamethasone suppression test
(DST) [78–82]. If oral DST dos not suppress the
cortisol secretion, initial diagnosis of Cushing
syndrome is reached. A plasma If oral DST dos
not suppress the cortisol secretion, initial diagnosis of Cushing syndrome is reached. A plasma
cortisol level after low dose DST less than 1,8mg/
dL excludes ACS; however, the cutoff value of
cortisol after the DST test changes between several guidelines [79, 80, 83]. Most of guidelines
accept 1.8–5.0 mg/dL cortisol level after low
dose DST is intermediate group to diagnose
ACS.Although more than 5mg/dL cortisol level
is diagnostic for ACS, NIH, AACE/AAES, AME,
and ESE recommend additional biochemical
tests in those patients for differential diagnosis.
The majority of ACS patients has not any evident
clinical symptoms but hypertension, glucose
intolerance, and bone mineral changings can be
associated with the syndrome.
About 41–92% of patients with ACS have a
mild to moderate hypertension [88]. It has also
been showed in a 15-year follow-up study that
ACS patients have increased cardiovascular morbidity (43% vs. 8.8%, p< 0.005) and mortality
(22.6% vs. 2.5%, p < 0.02) compared to
nonfunctional adrenal tumor patients [89, 90].
Impaired glucose tolerance or diabetes has been
detected to occur in 10–69% of patients with
ACS [91]. Both of the bone lose as trabecular and
cortical have been showed in ACS patients [92,
93]. A meta-analysis showed that the prevalence
of bone fracture is 63.6% in ACS patients [94].
21.10.2 Surgical Treatment
Two main treatment options for ACS are surveillance/medical management and surgery.
Nonoperative management includes surveillance and medical management of excess
236
M. Haciyanli et al.
cortisol- associated comorbidities if it is necessary.
Since ACS is not accepted as a precursor of
Cushing’s syndrome, whether those patients should
undergo adrenalectomy is a matter of debate.
In a meta-analysis of patients with ACS, adrenalectomy resulted in improvement only in
hypertension and diabetes when compared with
the medically managed ACS patients [95].
Another review showed improvement in lipid
metabolism, obesity, and osteoporosis after adrenalectomy in those patients [96].
Improvement of cardiovascular risk factors in
ACS patients after adrenalectomy is controversial and the long-term benets of adrenalectomy
have not been demonstrated yet. So it is still a
matter of debate that which patient will benet
from surgery.
The guidelines do not routinely recommend
adrenalectomy to all patients with ACS. The
AACE and American Association of Endocrine
Surgeons (AAES) recommend adrenalectomy
only in patients having ACS with worsening
abnormal glucose tolerance, dyslipidemia, hypertension, and osteoporosis [84].
The decision of surgical treatment must be
individualized for patients and presence of
comorbidities, end organ damage, and age of
patient, size and radiological features of tumor
may dictate the approach.
21.11 Adrenal Incidentaloma
The adrenal mass larger than 1cm detected incidentally in an imaging of patients for nonadrenal
disease is called adrenal incidentaloma (AI). The
lesions on imaging test of patients having cancer
or hereditary adrenal disorders are outside of this
denition [97]. The prevalence of AI is between 3
and 5% in imaging series [98]. The majority of
AI are unilateral but bilaterally disease can be
detected in approximately 15% of patients [97].
The major concern of a physician facing with
adrenal incidentaloma is whether those lesions
are functionally active or malignant. Although
most of AI are benign and nonfunctional (up to
80%), some are hormone active (overproduction
of cortisol, aldosterone, or catecholamine/metanephrine) or malignant.
A group of biochemical tests clarify the functional status of AI.Routine measurement of catecholamine, hypokalemia and hyperglycemia
screening and mineralocorticoid (in case of
hypertension and hypokalemia) evaluation have
to be done. The evaluation of hypercortisolism is
performed by 1mg overnight DST.The threshold
for diagnosing subclinical hypercortisolism
remains at 1.8μg/dL (50nmol/L), with 95% sensitivity and 80% specicity [84].
The main issue in the chapter is the patients
who need surgery for suspicion of malignancy.
The procedure is mostly diagnostic and therapeutic rather than prophylactic but in borderline
cases it can be accepted as prophylactic manner
which will be outlined.
The computed tomographic characteristics
(lipid content and washout dynamics) and size
are two important criteria for malignancy assessment since the needle biopsies have limited place
in the diagnosis of adrenal masses.
CT scan with non-contrast images gives
information about the size and lipid content of
the lesion, as well as the vascularity, contour and
the homogeneity, the presence of lymph nodes
and the invasion to adjacent tissues [98]. The
lipid content is inversely proportional with
malignancy. Hounseld units (HU) is indicative
for lipid content. A density >10 HU on the CT
scan has a sensitivity of 100% and a specicity
of 72% for diagnosing malignancy [99]. High
contrast washout at 15min is indicative of the
benign nature of an incidentaloma on contrast
CT [79, 99].
The diameter of the mass is another alerting
sign for the malignancies. The adrenocortical
cancer risk is 2%, 6%, and, 25% for the mass
smaller than 4cm, 4–6cm, and larger than 6cm,
respectively [100].
Surgery usually is not recommended for AI
less than 4cm and benign imaging features. The
follow-up strategies of those lesions (<4 cm,
homogeneous and with low density (<10HU)) differ in guidelines of ESE and AACE/AAES. ESE
does not recommend follow-up for those patients.
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