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A. Valeri et al.
debulking purpose is considered as an option to achieve better symptom control
even in metastatic patients. Repeated surgery in recurrent tumors is also considered
[34]. Mitotane and streptozotocin are the most used drugs for chemotherapy
although a combination with etoposide, doxorubicin, and cisplatin on top of mitotane has been proposed as a rst-line therapy following the results of a large prospective randomized controlled trial [37]. Radiotherapy is also associated in
advanced disease [38]. Adrenalectomy is the only possible cure in ACC, and the
overall survival varies signicantly according to stage and R1-2 resection at primary surgery. Radical R0 adrenalectomy instead achieves signicantly better prognosis with survival of decades after surgery. As in previous experience, age did not
have a great impact on survival and therefore also elderly patients can be cured
with radical surgery in non-advanced stages [34]. Prognosis is usually affected by
local recurrence and the more sensitive prognostic factors after repeated surgery
were time to rst recurrence and radical surgery [39]. Histopathological diagnosis
of ACC is based on specic parameters, and among them the classical Weiss score
considers the observation of at least three of the nine criteria (grade 3 or 4 nuclear
grade with enlarged, oval to lobulated nuclei with coarsely granular to hyperchromatic chromatin and easily discernible, prominent nucleoli; mitotic grade>5/50
HPFs; atypical mitoses; clear cells comprising 25% or less of the tumor; diffuse
architecture greater than one third of the tumor; necrosis; invasion of venous structures; invasion of sinusoidal structures; invasion of the tumor capsule) [40, 41] or
in a modied revision only ve of them (mitotic grade; percent of clear cells comprising the tumor; abnormal mitoses; necrosis; capsular invasion) [42]. The
European Network for the Study of Adrenal Tumors staging system denes stage
I, ACC ≤5cm in the largest diameter and conned to the adrenal gland; stage II,
ACC >5cm without extra-adrenal invasion; stage III, presence of positive lymph
nodes, inltration to the surrounding tissue, or vascular tumor extension; and stage
IV, distant metastasis. This staging system was considered prognostically superior
to the International Union Against Cancer staging system [43].
8.5 Metastases
The adrenal gland is the fourth most common organ to be involved by metastases
after the lung, liver, and bone. Metastases to adrenal glands usually originate from
malignancies of the gastrointestinal district, lung, breast, prostate, kidney, liver,
and melanoma. Carcinoma is the histological type mostly represented. Isolated
metastases to adrenal glands are rare, being adrenal secondarism usually associated with multiple organ metastases. Adrenal metastases appear as soft tissue
lesions on CT either replacing the gland or as its diffuse enlargement. Typically
adrenal metastases show signicant attenuation on unenhanced CT and do not
produce signal drop on opposed phase images on MRI.These criteria show a high
degree of sensitivity and specicity to permit a diagnostic differentiation from
adenomas. Furthermore FDG- PET CT can increase accuracy since usually metastases are hypermetabolic compared to adenomas. Progressive increase in size at
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short-term follow-up of an indeterminate lesion in a cancer patient is suggestive
of metastatic secondarism [44]. The management of adrenal metastases includes
surgery, local ablative treatments, radiotherapy, chemotherapy, and palliative
treatment. The strategy depends on the different clinical situations, tumor type,
stage, synchronous metastases in other organs, and local features of the adrenal
secondarism. Surgery presents a specic indication in selected patients with isolated adrenal metastases, and in this setting, a survival benet after resection has
been shown [45]. Laparoscopic adrenalectomy has been shown to improve
patients’ morbidity and to reduce hospitalization with equivalent oncological outcome compared to the open resection technique for ACC and also for adrenal
metastases. It must be considered as the rst option approach to adrenal metastases but still has clear contraindications in larger lesions with a 6cm cutoff [46,
47]. Radiotherapy has been used with palliative intent with good response rates
reported and limited toxicity, especially in terms of pain relief. Other therapeutic
options include radiofrequency ablation, microwave ablation, and stereotactic
body radiation therapy [48].
8.6 Incidentaloma
The current prevalence of unsuspected adrenal masses is approximately 3–4% in
abdominal CT scan series. This rate is probably underestimated because adrenal
adenomas were found in up to 10% of patients who died without any premortem
suspicion of adrenal disease. Incidentaloma is slightly more frequent in women [49,
50]. While the incidence of incidentalomas increases with age, it can be seen across
all age groups with high incidence in fth and sixth decades [35]. Although an inci-
dentaloma is nearly always benign with nonfunctioning adenomas being the most
common tumors [51], usually malignant adrenal incidentalomas are metastatic in
origin [52]. Therefore, accurate diagnosis of malignant adrenocortical tumors, particularly distinguishing ACC from adrenal adenomas, is essential for the management, but correct diagnosis is challenging. Size and heterogeneity remain the most
predictive features of malignancy, as more than 4cm in size and presence of hemorrhage, necrosis, heterogeneous contrast enhancement, and lack of contrast washout
favor malignancy. Currently adrenal incidentalomas are considered to be the most
common adrenal lesion; increased detection has been attributed to the increased
availability of CT and improvements in CT technology enabling detection of even
small adrenal lesions. Adrenal incidentalomas are adrenal lesions greater than 1cm
in size detected incidentally on imaging, most commonly CT and occasionally on
ultrasound, MRI, or PET-CT. Unenhanced CT is recommended as the initial test
with the use of an attenuation value of 10 Hounseld units to differentiate between
adenomas and non-adenomas [51]. Seemingly, nonfunctioning adenomas are usually asymptomatic, but indeed they may present minimal secretory activity which
may cause subclinical forms of Cushing’s syndrome, catecholamine excess, hyperaldosteronism, or hyperandrogenism. As shown in a large Italian series, often the
discovery of an adrenal incidentaloma may lead to the detection of a remarkable
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A. Valeri et al.
number of subclinical hormone-producing tumors and could result in an early cure
of clinically silent hypercortisolism, silent catecholamine hypersecretion, and rarely
unsuspected hyperaldosteronism. Although patients with Cushing’s syndrome have
clearly established complications, the morbidity of patients with subclinical disease
is less clear, and controversy exists around the risk of progression from subclinical
to overt hypercortisolism, but subclinical forms might also be associated with
increased risk for hypertension, diabetes, obesity, or osteoporosis. An early diagnosis of pheochromocytoma, by determination of urinary catecholamines in all adrenal masses, is important to avoid future hypertensive complications and an eventual
perioperative mortality, which is possible in medically untreated patients with
unrecognized pheochromocytoma before surgery. Not all patients with silent hyperaldosteronism had slightly decreased potassium levels, but they might have hypertension and suppressed upright PRA levels [35, 53]. After prevalent nonfunctioning
adenomas, other benign masses like cysts, myelolipoma, and hemorrhage also have
characteristic imaging features and can be differentiated from the other conditions.
However, in a patient with a known underlying malignancy, the probability of incidentaloma being malignant substantially increases, and 50–70% of adrenal masses
are likely to be metastases [30, 54].
A myelolipoma is an uncommon benign lesion composed of mature fat inter-
spersed with marrow-like hematopoietic tissue. It occurs with a prevalence of 0.08–
0.2% and it is usually unilateral and asymptomatic. The size varies from 2 to more
than 10cm, and attenuation depends on the amount of fat with the presence of calcication. On ultrasound myelolipoma is visualized as heterogeneously hyperechoic lesion owing to the presence of variable amounts of fatty and myeloid
component. CT remains the diagnostic modality of choice which depicts the presence of fat as low-attenuation areas. The areas of fat are hyperintense on T1- and
T2-weighted images on MRI with loss of signal on fat-suppressed sequences.
Lipoma and angiomyolipoma are other fat-containing lesions which must be considered for differential diagnosis [55].
Adrenal cysts are incidentally detected lesions and are usually asymptomatic.
Ultrasound shows a well-dened lesion with anechoic contents in uncomplicated
cysts, and CT demonstrates the exact nature and extent of the lesion. They may
appear hyperdense in the case of hemorrhage or infection within and show no
enhancement on post contrast scan [56].
Adrenal hemorrhage is usually encountered in patients with blunt abdominal
trauma where it affects the right adrenal more than the left. Attenuation on CT
depends on the stage of hemorrhage, higher attenuation in the acute stage becoming
isodense to hypodense as the clot liquees and may calcify in the chronic stage [56].
The nal diagnosis is most frequently inferred from stability of the adrenal mass
over variable periods of observation (at least 6months). Adrenal incidentaloma is
not a uniform disease, and its natural history varies depending on the pathological
classication of the adrenal mass. It is obvious that primary malignant adrenal
tumors, and pheochromocytomas, can signicantly affect patients’ health and
patients’ outcome, and which can be greatly improved by prompt adrenalectomy.
Adrenalectomy is usually recommended to all patients with subclinical CS or PH
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and to all patients without endocrine activity but with mass size >4cm or a size
increasing by >1cm during the follow-up [53].
8.7 Adrenalectomy inElderly Patients: Indications
andSurgical Technique
In recent years the diagnosis of neoplasms in the elderly has increased because of
the rise in life expectancy and the implementation of routine screening exams [30].
Elderly patients are physically fragile due to their attenuated systemic response to
surgical stress and the frequent presence of comorbidities. In the elderly the surgery
of adrenal glands had been shown to be feasible, but the surgical outcomes may be
worse due to the fact that these patients are more prone to postoperative complications and have a slower recovery. It is important to consider that in nonspecialist
centers, surgeons may be hesitant to perform surgery in elderly patients because of
their higher risk of perioperative complications (due to a reduced breathing capacity, renal function, and resting cardiac output) and death [54, 55] and that this kind
of surgery in such fragile patients requires maximum effort, focusing on strict control of comorbidities and complete preoperative care in order to facilitate a quicker
surgical recovery with fewer complications.
In the elderly the clinical features of surgical diseases of the adrenal glands do
not basically differ from those found in younger patient [56].
The history of adrenal surgery is long-standing. In 1914 the rst planned adrenalectomy was performed by Perry Sargent [57]; meanwhile, the rst ank approach
for pheochromocytoma was performed by Dr. Charles Mayo in 1927. In 1992,
instead, Michael Gagner performed the rst laparoscopic procedure of the adrenal
gland [58] and since then there has been a radical change in the management of
adrenal tumors.
With the introduction of laparoscopic adrenalectomy, there was a reduction of
the length of hospital stay, healthcare cost, wound complications, and blood loss
and an improvement in the patient’s outcome [
scopic approach is considered the “gold standard” therapy for the majority of adrenal gland tumors.
Different studies [29, 56, 62] have demonstrated the feasibility and the safety of
the laparoscopic approach in elderly patients even if this may be associated with
postoperative complications or a more frequent open conversion rate [63].
59–61]; in fact, currently the laparo-
8.8 Indications forSurgery
The indications for adrenalectomy concern the presence of a functional tumor associated with hormone secretion (PA, CS, PH, and PG), the presence of a nonfunctional tumor associated with a suspicion of malignancy or ACC [64], and the
presence of adrenal metastases from primary lesions of the lung, kidney, and breast,
melanoma, and the gastrointestinal tract and incidentalomas [65].
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A. Valeri et al.
8.9 Open Adrenalectomy
The open adrenalectomy has been for decades the only surgical approach to adrenal
tumors; meanwhile currently it is generally performed in the presence of general contraindications to laparoscopy or in presence of large lesions (>12cm in diameter) or
malignant tumor with an invasion of the adjacent structures. Different accesses are
possible in order to perform open adrenalectomy: transperitoneal approach (anterior,
median, transverse, subcostal), extrapleural-extraperitoneal approach (lateral, posterior), and transpleural-transdiaphragmatic approach (trans-thoraco-abdominal).
It is important to consider that all approaches that limit the access to the peritoneal cavity decrease the rates of postoperative ileus, while the extraperitoneal
approaches are associated with high rates of neuromuscular morbidity such as
chronic pain (14%), laxity in ank muscles (30%), and ank numbness (10%) [66].
8.10 Laparoscopic Adrenalectomy
Different laparoscopic approaches have been described, such as the anterior
approach (with patient in supine position), the lateral approach (with patient in lateral position), and a retroperitoneoscopic approach (with patient in prone or lateral
position) [67–70].
The most widely practiced approach is the lateral transabdominal one because it
provides a good exposure of the adrenal gland and surrounding structures and provides the surgeon with the precise anatomic landmark together with a safe control
of vascular structures [67, 68].
The anterior transabdominal adrenalectomy is less employed because the conventional abdominal laparoscopic view of the abdomen leads to longer operatory
times and greater number of ports used [71, 72].
The retroperitoneoscopic approaches, instead, allow a direct access to the adrenal glands avoiding the peritoneal cavity but have important limitations in tumor
size and in longer operating times [73–76].
8.11 Selection ofPatients
The “gold standard” treatment for adrenal tumors is laparoscopic adrenalectomy
[77], and for this reason, all functional tumors including pheochromocytoma are
candidates for a laparoscopic approach in the absence of other contraindications.
The open approach is recommended in patients with evidence at preoperative imaging studies of malignancy with local invasion of adjacent structures. Another important parameter is the size of the tumor, but it is not an absolute contraindication to a
laparoscopic resection; in actual fact, tumor size greater than 6cm is not an absolute
contraindication to laparoscopy [47, 78].
In the adrenal gland surgery, it is important to consider that a multidisciplinary approach, which comprises surgeons, anesthesiologists, endocrinologists,
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oncologists, plays an important role in the management of elderly patients and
that the success of the procedure is also related to surgeon experience and hospital
volume.
Conclusions
Some studies conrmed that laparoscopic adrenalectomy in elderly patients is
safe and effective and decreases hospital stays, operative blood loss, and wound
complications. Age alone should not be considered a real contraindication to
laparoscopic adrenalectomy, while the real contraindications to this technique
are represented by large tumors, malignant tumor with an invasion of the adja-
cent structures, and the general contraindications to laparoscopy, whereas regard-
ing the preoperative care, it is important to adopt several actions in order to
facilitate a quicker surgical recovery associated with fewer complications.
Usually in the preoperative management of elderly patients, short-acting selec-
tive alpha-blockers are preferred in order to avoid prolonged postoperative hypo-
tension [79]. Furthermore, in elderly patients a preoperative bowel preparation is
judicious in order to prevent hydric and electrolyte disturbances and to minimize
the risks of colonic bacterial translocation [80]. Moreover, it is recommended to
introduce an early anticoagulation therapy in order to reduce the risk of postop-
erative pulmonary embolism and to institute an intense pulmonary rehabilitation
in order to reduce the risk of other postoperative pulmonary complications.
In conclusion, a meticulous preparation for surgery is crucial among the
elderly patients, and particular attention should be focused on maintaining the
balance between the adrenal disease and comorbidities and on the early management of any postoperative complications.
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