Adrenal incidentaloma: Surgical update
M. Guerrieri1, A. De Sanctis1, F. Crosta1, G. Arnaldi2, M. Boscaro2, G. Lezoche3, and R. Campagnacci1
1Department of General Surgery; 2Division of Endocrinology, Department of Internal Medicine, Polytechnical University of Marche, “Umberto I” Hospital, Ancona; 3”Paride Stefanini” Department of Surgery, 2nd Surgical Institute, “La Sapienza” University, Rome, Italy
ABSTRACT. Nowadays, the role of surgery in the treatment of adrenal incidentalomas (Al), con- sidering their biologic behavior, is still debated. Surgery is mandatory in cases of hyperfunction- ing adrenal masses, in the presence of suspect radiological malignancy, in cases of discordant computed tomography (CT) and scintigraphy findings and when the maximum diameter is 4 cm or more. On the other hand, studies have sug- gested relative inaccuracy of conventional CT in evaluating the size. The aim of this paper was to evaluate the safety and effectiveness of laparo- scopic adrenalectomy (LA) in the treatment of Al by reviewing our experience. Over the period from 1995 to 2005 we laparoscopically managed 78 Al by anterior transperitoneal approach. Two LA (2.6%) were converted to open surgery. Nei-
ther intra- nor post-operative major complications were observed. The mean size of lesions was 5.5 cm (range 3-9). Twenty-one large adrenal lesions (exceeding 6 cm) were removed (27%). Defini- tive histology resulted as follows: adrenocortical adenoma (63), pheochromocytoma (5), nodular hyperplasia (4), myelolipoma (3), cysts (2), and adrenocortical carcinoma (1, with a size of 3 cm). The patients were followed-up by hormonal and radiological evaluation every 12 months (6 for ma- lignancy); their follow-up (median 60.4 months, range 6-123) was uneventful. Also larger Al were treated safely. Laparoscopy has been safe and ef- fective in the treatment of Al in our experience, according to specific literature.
(J. Endocrinol. Invest. 30: 200-204, 2007) @2007, Editrice Kurtis
INTRODUCTION
Since the introduction and widespread use of high- definition imaging tools, such as magnetic reso- nance (MRI) or computed tomography (CT), a new lesion concept on the adrenal field has been more frequently reported. “Incidentaloma” or “adrenalo- ma”, as well as “silent adrenal tumor”, summarize both incidental reports and clinical signs as in ab- sence of lesion (1, 2). Incidental finding of a mass of the adrenal gland involves the planning of a series of specific exams in order to define the malignant potential and the overall adrenal hormonal status of a patient (3). Only after this evaluation may the term “adrenal incidentaloma” (Al) be used.
The management of clinically unapparent adrenal masses is a complex problem, considering their bio- logic behavior. In most cases, conservative treatment is justified because the growth tendency of these tu- mors is slow, frequently remaining hormonally inac- tive in long-term follow-up. Surgical treatment of in- cidentalomas should be reserved for a lesion having clinical expression, as well as in all cases, apart from symptoms, measuring over 4 cm diameter, in which the rate of malignancy, or the progress toward it, are not negligible (4-6). On the other hand, some stud- ies pointed out the relative inaccuracy of conven- tional CT and MRI in evaluating the size: radiological examination consistently underestimated adrenal tu- mor size, particularly for tumors measuring less than 3 cm (7-9). Conversely, the low risk of adrenalectomy especially via the laparoscopic approach can provide an early definitive diagnosis and treatment, avoid- ing radiological underestimation and the cost of a long-term follow-up as required by the conservative management of these tumors.
In 1992 Gagner et al. reported the first laparoscopic adrenalectomy (LA) (10). Since then, a minimally invasive approach to the adrenal gland has increas-
Key-words: Adrenal incidentalomas, operative criteria, laparoscopy, ante- rior approach, adrenal carcinoma.
Correspondence: M. Guerrieri, MD, Department of General Surgery, Poly- technical University of Marche, Umberto I Hospital, Via Conca 71, 60020 Ancona, Italy.
E-mail: guerrieri.m@libero.it Accepted September 19, 2006.
ingly been used in high skilled laparoscopic centers, revealing it as a safe and effective technique show- ing the well known benefits of laparoscopy such as a comfortable post-operative course, short hospital stay, rapid return to daily activities and good cos- metic result. Both anatomic location of the gland, which is deep in the abdomen, and potential life- threatening influence on blood pressure and cardiac rhythm from functional tumors such as pheochromo- cytoma have long been topics of discussion among surgeons. It appears that LA is becoming the gold standard for adrenalectomy (11-17). Some contro- versy remains regarding the safety and the effective- ness of LA for large lesions and malignancy. Several techniques of LA have been described, as anterior or lateral transperitoneal, posterior retroperitoneal and anterior transperitoneal submesocolic access (18-22). Usually, we prefer the anterior transperito- neal approach in the supine position (20, 23).
The aim of our study was to report the results of LA in terms of safety and effectiveness for Al, larger than 4 cm or, selectively, smaller, but demonstrating suspect radiological findings or size increase during consecutive imaging exams.
MATERIALS AND METHODS
From January 1995 until April 2005, 78 patients with Al were referred to our department. Fifty patients were females and 28 males, with an average age of 53.8 yr (range 19-75). Fifty-one incidentalomas were located in the right gland and 27 in the left. Fifty-four patients (69.2%) did not present any evident symptoms depending on adrenal disease, while 13 (16.7%) complained of vague abdominal pain, 9 (11.5%) suffered from blood hyperten- sion and 2 (2.6%) from glucose intolerance. Blood hypertension study did not clearly pre-operatively reveal endocrine or vascular causes, and therefore was defined as essential. Glucose intoler- ance was not further investigated.
In order to establish the adrenal functional status all patients under- went hormonal evaluation. Diurnal rhythm of plasma cortisol, 24-h urinary free cortisol (UFC), plasma ACTH, DHEAS, 17-hydroxypro- gesterone (17-OHP), testosterone, androstenedione, supine and upright renin activity and aldosterone, 24-h urinary catecholamine (epinephrine, norepinephrine and metanephrines) were evaluated. Plasma metanephrines were not used to assess functional status. Hormonal dynamic tests included an overnight 1-mg dexametha- sone suppression test (DST) and in some cases an 8-mg DST, CRH stimulation test and a short ACTH stimulation test. The diagnosis of adrenal Cushing’s syndrome, aldosterone-producing adenoma and pheochromocytomas was based on: elevated UFC, abnormal serum cortical 24-h rhythm, inadequate cortisol suppression after 1- and 8-mg dexametasona and low plasma ACTH (basal and after CRH), high plasma aldosterone/plasma renin activity (PRA) ratio (>40) and unsuppressed aldosterone after sodium load, elevated urinary catecholamines and metanephrines and in some cases high plasma catecholamines. Recently the concept of “sub-clinical Cushing’s syndrome” was added, defined by the presence of two or more abnormal functional tests of the hypothalamic-pituitary-
adrenal axis in patients without most of the classic clinical stigmata of hypercortisolism. According to the definition of Al, exclusion criteria a priori were severe or paroxysmal hypertension, severe hypokalemia and clinical signs of hypercorticolism or hyperandro- genism. In the absence of specific signs and/or symptoms of hor- mone excess, normal hypothalamus-pituitary-adrenal axis function or not more than one abnormal test and morphological aspect of the tumor compatible with cortical adenoma, a diagnosis of non- hypersecretory adrenocortical adenoma was made. Patients were also studied with CT scan and/or MR. An attenuation value of 10 or less Hounsfield Units (HU) on unenhanced CT scan, and 40 or less HU on enhanced CT scan were considered as suggestive of benign adrenocortical adenoma. Other CT and/or MRI features considered as suggestive of benign lesion were: a size less than 4.0 cm, round/ oval shape, homogeneous content and well-defined margins and isointense on T2 weighted. Experienced radiologists reviewed CT and/or MRI scans and a presumptive diagnosis of benign tumor (adrenocortical adenoma, cyst, myelolipoma) was made. On the contrary, when CT or MRI features of the mass were large, with an inhomogeneous content and irregular shape, a suspect malignant pattern was assumed. Regarding our series, four normal blood pressure patients presented 24-h urinary cathecolamines slightly higher than normal, and three sub-clinical Cushing’s syndrome. Based on these data and above mentioned criteria, the 78 patients operated on with LA in this series revealed adrenal lesion over 4 cm of diameter or smaller but having imaging pattern of suspect malig- nancy and masses sub-clinically secreting (Table 1). Empirically, a le- sion increasing over 50% of its size in 4-6 months of imaging control was judged to need removing. Full informed consent for surgery and laparoscopic technique was obtained from each subject. In all cases the surgical procedure was carried out under general an- esthesia. Surgical approach was anterior transperitoneal in the su- pine decubitus position. Two left adrenalectomies were performed
| Sex | · Male |
|---|---|
| Age (yr) | · < 50 |
| Functional status | · Elevated value of DHEAS |
| Tumor size (cm) | . 3-6: low-risk · >6: high-risk |
| Increased diameter (cm) | · >1.5-2 over 6 months · Irregular margins · Presence of necrosis, hemorrhage, calcification . Non-homogeneous density with marked enhancement after in- travenous contrast |
| CT scan | |
| MRI | . Low signal intensity and T1-weight- ed images . High signal intensity and T2-weight- ed images |
| Scintigraphy | . A "discordant pattern" compared to CT images, demonstrating decreased or absent radio-cholesterol uptake by the affected adrenal gland |
CT: computed tomography; MRI: magnetic resonance imaging.
with a submesocolic access: an alternative anterior transperitoneal access to the left adrenal gland with minimal anatomical dissection, previously described (20, 23, 26).
RESULTS
Average operative time was 91 min (range 50-150) and 121 (range 90-200) for right and left LA, respec- tively. Eight patients underwent associate procedures: 6 cholecystectomies and 1 left ovariectomy (5 right adrenalectomy and 2 left contextual), 1 right renal cyst capitonnage (on right adrenalectomy). In two patients (2.6%) the procedure was converted to open adrenal- ectomy because of bleeding in one, and obesity in the other. Neither intra- nor post-operative major compli- cations occurred. Five patients in whom histology revealed pheochromocytoma did not present blood pressure and/or cardiac rhythm abnormality during surgery. As minor complications 1 port site infection and 1 port site hematoma occurred. Mobilization and oral intake were on the first post-operative day. All patients were able to resume their daily activity within 7 days of the operation. Average post-operative hos- pital stay was 2.7 days (range 1-7).
The mean size of adrenal masses was 5.5 cm (range 3-9), with a mean weight of 38 g (range 7.34-102.27). Twenty-one (27%) adrenal lesions removed exceeded 6 cm of diameter. The same experienced patholo- gist reviewed pathological specimens. Histological diagnosis of adrenocortical carcinoma was based according to Weiss criteria (BIB) (24, 25). Definitive histology revealed: adrenocortical adenoma (63), cyst (2), nodular hyperplasia (4), myelolipoma (3), pheochromocytoma (5) and adrenocortical carcinoma (1). The case of the carcinoma was observed in a 63-yr- old female, located in the left gland with a diameter of 2.5X3 cm. The adrenal mass was non-functioning, but of radiological malignant pattern (not homogeneous content). Indeed, despite one of the CT scan suspect- ing malignancy factors being found in three cases, in only one of those was the histology response carci- noma. At a mean follow-up of 60.4 months (range 6-123), the patients underwent adrenalectomy for secreting lesions with hormonal exams as a rule. The patient whose histology gave evidence for carcinoma was disease free at 18 months of follow-up.
DISCUSSION
Incidentalomas are a well-defined group of lesions of the adrenal gland increasingly detected in recent years because of US CT scan and MR wider use. Overall rate of unexpected adrenal lesions found during any type of radiological test is about 9%, being for CT only approximately 4% (27, 28). Post-
mortem examination studies report a rate of undiag- nosed adrenal mass ranging from 1.4 to 8.7%; usual- ly small lesions measuring about 2 cm, exceptionally, 0.025% of cases, over 6 cm (27, 29). Pathological findings from many authors are generally in agree- ment: 60% of cases are adrenocortical adenoma, 5-10% pheochromocytoma, 8% myelolipoma, 2-3% ganglioneuroma, 5-6% cystic lesions, 10% malignant primitive and 2-3% malignant metastasis lesions (5). In about 80% of incidentalomas, the tumors are non hypersecreting adenomas (5).
Whenever an unexpected adrenal mass is found, a clinical and laboratory specific evaluation should be carried out, in order to exclude malignancy or hormonal activity. Moreover, the patient should be investigated for symptoms related to an adrenal tu- mor, keeping in mind that the absence of symptoms is not a reliable requirement to exclude adrenal tumor activity. Subclinical Cushing’s syndrome is the most frequent hormonal abnormality diagnosed in patients with Al (5-10%). Patients with silent pheochromocyto- mas were also frequent in Al with a prevalence of 5%. Finally, approximately 1% of all patients with inciden- taloma has a hyperaldosteronism. Surgical removal is considered for the above mentioned lesion. Moreo- ver, LA in a case of pheochromocytoma, pre-Cush- ing and aldosteronism might avoid the long-lasting effects from the altered hormonal status (30). In our series the dexamethasone suppression and urinary cortisole tests allowed us to diagnose 3 patients with subclinical Cushing’s syndrome and 4 with pheochro- mocytoma with normal blood pressure.
Adrenal carcinoma is a rare entity in otherwise healthy patients. However, in a young subject, less than 50 yr of age, with previous carcinoma, or having a secreting adrenal mass, or with an adrenal non-se- creting incidental lesion over 4 cm, the risk of adrenal carcinoma rises to 20% (31, 32). The risk factors for the adrenal carcinoma are summarized in Table 2. Adrenal masses with back pain, or weight loss, sug- gest locally advanced disease with a well-founded suspect of carcinoma. US is at present the first-line
| Functional status >normal | · 7 (4 cathecolamines, 3 subclini- cal Cushing) |
| Tumor size | · >4 cm (69 patients) · < 4 cm (9 patients, 7 secreting masses) |
| Increased diameter 1.5 cm over six months | · 1 (histology: benign) |
| CT scan malignancy suspect | · 3 (histology: 2 benign, 1 carci- noma) |
imaging examination for mainly abdominal diseases, because of its non-invasiveness and low cost advan- tages. More accurate and expensive imaging proce- dures such as CT and MR represent the second-line diagnostic procedures. These allow both casual de- tection of adrenal lesion and information concerning their likely malignancy (31). In detail, CT scan has a 95% accuracy evaluating lesions located in the adre- nal region, finding cystic or solid masses of 0.5 cm. Moreover, CT reveals peculiarities of malignancy, such as the lesion margins or intralesional-calcified areas (31). Scintigraphy with 1311-6 beta-norcho- lesterol (NP59) and with 131| metabenzilguanidine (MIBG) are used to characterize adrenocortical and adrenomedullar lesions, respectively (28, 31). CT da- ta compared to scintigraphic results may clarify the pre-operative suspect of malignancy. Sophisticated imaging data apart, the majority of authors’ results admit as a paramount factor of malignancy a lesion size of over 4 cm, with adrenal adenomas generally inferior to 4 cm diameter. Notwithstanding, malig- nant Al measuring less than 4 cm are reported in the literature. In these cases surgical removal allows better oncological results than in larger and more advanced cases (32, 33). Other authors admitted the change towards malignancy of an initially benign lesion (34). However, there seem to be grounds for considering surgery for cases of non-secreting incidentalomas over 3 cm in young patients, and lesions under 3 cm if secreting and requiring long- term drug therapy. On the one hand, the long-term survey by means of periodically repeated imaging evaluation such as CT scan or MRI, and on the other hand the foreseeable sine die drug medication may play a role toward surgical option. Nevertheless it remains a matter of ethic discussion whether mini- mally invasive surgery, according to endocrinology and imaging data, may lead to wide indication of adrenalectomy for adrenal incidentally found lesions previously followed up in time. In our experience, the well known advantages of minimal access sur- gery have been confirmed. Patients, experiencing minimal or absent pain, were ambulating freely and tolerated a liquid diet on their first post-operative day, and were soon discharged. In the present series of over 78 LA, the transperitoneal anterior approach has proven to be safe and effective because of visu- alization and recognition of the fundamental ana- tomic landmarks, including large vessels (cava vein on the right, renal vein and aorta on the left). The surgical technique was the same used for benign disease and suspected malignant lesions. For both indications, the manipulation prior to adrenal vein legation was minimal, closure of the adrenal vein was always attempted as the first step of the proce-
dure, and the gland was removed together with the per-adrenal fatty tissue. The laparoscopic transab- dominal anterior access with the patient in a supine position provides an excellent vision of the perito- neal cavity for preliminary diagnostic laparoscop- ies, including the controlateral side, which can be explored with intraoperative US. Furthermore it also constitutes an advantage when rapid conversion to open surgery is required in accidental cases of major bleeding. Moreover, the supine position allows the performance of associated surgical procedures such as cholecystectomy and ovariectomy and other op- erations through the same port sites. In our study, as also previously reported, adrenal lesions larger than 6 cm have been removed (18, 20, 23). In these cases the laparoscopic removal was performed with a surgical approach which takes into account onco- logical principles and includes the following: early ligature of the main adrenal vein, whereas by lateral flank or posterior approach it can be performed only after wide mobilization of the gland, no “squeeze” technique and no direct manipulation of the gland before the complete devascularization, and removal of the gland with an endo-bag. These items are re- markable not only for oncological strategy but also for functional adenomas and particularly for suspect pheochromocytomas. In this case, the left submeso- colic access reduces the adverse effects related to the manipulation of pheochromocytomas and the risk of spillage in case of malignancy, allowing the middle adrenal vein closure as a first step of the pro- cedure with minimal gland manipulation. Finally, in treating Al, this approach allows very minimal dissec- tion in reaching and removing the adrenal gland. In our patients LA for incidentaloma was demonstrat- ed as a safe and effective procedure. According to the literature data, we agree on the assumption that at present adrenal masses over 4 cm in diameter are eligible for surgery. Nonetheless, keeping in mind the reported cases of small size adrenal carcinoma and the relative inaccuracy of conventional CT and MRI in evaluating the size, we also think that selected cases of small incidentalomas of less than 4 cm, but secret- ing, even if subclinically, or suspected of potential malignancy amenable to LA, should be included.
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