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Adrenal Incidentaloma: An Overview of Clinical and Epidemiological Data from the National Italian Study Group

BACKGROUND The incidental discovery of an adrenal mass raises the problem of distinguishing the frequent benign masses from the infrequent malignant ones that require surgery. At present, univocal guidelines to approach this problem are not available. The aim of the present study was to perform a multicentric retrospective analysis of adrenal masses incidentally discovered (adrenal incidentalomas). PATIENTS AND METHODS Hospital records of adrenal incidentalomas diagnosed over a 15-year period in 29 surgical and medical centers in Italy were scrutinized. Collected cases were 1,013, and 887 were analyzed. RESULTS The majority of patients were in the 5th and 6th decade and females were predominantly affected. The frequency of adrenocortical cancer was 12% among operated patients (316 cases). The tumor diameter was highly correlated with the risk of malignancy, as well as the CT characteristics such as density, shape and margins. The frequency of pheochromocytoma was 10% among operated patients. CONCLUSIONS The occurrence of incidentally discovered adrenocortical carcinomas and pheochromocytomas is not rare. Evaluation of the mass size and CT characteristics are simple and effective methods to differentiate malignant lesions. Biochemical screening for pheochromocytoma is mandatory before surgery.

Immunohistochemical assessment of Ki-67 in the differential diagnosis of adrenocortical tumors

OBJECTIVES To evaluate the utility of Ki-67 immunohistochemical analysis in the differential diagnosis between benign and malignant adrenocortical neoplasms. METHODS Tissue specimens were obtained from 37 patients referred to our institute from 1990 to 1999. The indications for adrenalectomy were adrenal-dependent Cushing syndrome (n = 9), hyperandrogenism (n = 1), mineralocorticoid excess (n = 8), and nonfunctioning adrenal masses (n = 19). The histologic diagnosis was cortical adenoma in 26 of 37 patients and cortical carcinoma in the remainder. Normal adrenal glands were obtained from subjects who underwent radical nephrectomy because of initial renal carcinoma. Immunohistochemical analysis was performed using the monoclonal antibody anti-Ki-67 (clone MIB-1). The Ki-67 labeling index was expressed as the number of positive cells per 1000 cells.Results. The average Ki-67 expression was 2.0 per thousand +/- 1.2 per thousand (SD) in normal adrenal glands, 11.3 per thousand +/- 16.0 per thousand in adenomas, and 185.8 per thousand +/- 60.3 per thousand in carcinomas (P <0.0001). A threshold value of the Ki-67 labeling index between 70 per thousand and 90 per thousand reliably separated adenoma from carcinoma. A significant inverse correlation was found between Ki-67 expression and overall survival in patients with adrenal carcinoma (r = -0.74, P = 0.009). CONCLUSIONS Immunohistochemical assessment of the nuclear antigen Ki-67 can be useful in the differential diagnosis between adrenocortical adenoma and carcinoma. High levels of Ki-67 seem to indicate patients with adrenocortical cancer with a worse prognosis.

Cyclic Cushing’s syndrome due to ectopic ACTH secretion by an adrenal pheochromocytoma

Pheochromocytoma is a rare cause of ectopic Cushing’s syndrome. We report on such a patient in whom ectopic ACTH secretion displayed a cyclic pattern. A 35-year-old woman was referred to us with a diagnosis of ACTH-dependent Cushing’s syndrome. A 3.3 cm left-sided adrenal mass was noted at abdominal computerized tomography. At admission, clinical and hormonal data were unrewarding, so it was decided to continue to observe the patient. Four months later, she became symptomatic with hypertensive and psychotic crises and glycemic decompensation. By that time, a full-blown Cushing picture was evident. Severe hypercortisolism was documented with urinary free Cortisol ranging 1500–2200 μg/24 h, serum Cortisol 143–160 μg/dl and plasma ACTH 167–218 pg/ml. Neither ACTH nor Cortisol values were significantly modified after high-dose dexamethasone, oCRH or metyrapone. Urinary catecholamine and vanilyl mandelic acid excretion were moderately elevated. Chest CT and total body MIBG scan were negative and magnetic resonance of the sella region was inconclusive. No center to periphery ACTH gradient was observed by inferior petrosal sinus catheterization, whereas a significant left to right gradient was found on selective adrenal vein catheterization. A left adrenalectomy was performed and a 4 cm medullary neoplasia was removed. The cells were immunostained for ACTH, neuron-specific enolase and A chromogranin. Signs and symptoms of Cushing’s syndrome resolved with normalization of basal and dynamic endocrine evaluations. The patient is considered cured 10 months after surgery.

The limited value of the desmopressin test in the diagnostic approach to Cushing's syndrome.

OBJECTIVE The desmopressin test is generally regarded as an alternative to the CRH test but it is unclear whether desmopressin is as effective as CRH in the differential diagnosis of ACTH‐dependent Cushings syndrome. However, a precise assessment of the operating characteristics of the desmopressin test in comparison with the CRH test has not been reported. The aim of the present study was to make a comparative evaluation of desmopressin and CRH tests in a consecutive cohort of patients with ACTH‐dependent Cushings syndrome and in a group of healthy subjects.

Bilateral adrenalectomy for Cushing’s syndrome: A comparison between laparoscopy and open surgery

We report our experience with bilateral adrenalectomy for treatment of Cushing’s syndrome and we compare the outcome of laparoscopy with open surgery in terms of effectiveness and safety. A series of 23 patients underwent bilateral adrenalectomy for treatment of Cushing’s syndrome [Cushing’s disease in 16, ectopic ACTH syndrome in 2, and ACTH-independent macronodular adrenal hyperplasia (AIMAH) in 5 cases]. From 1993 to 1996, all patients were treated using an open approach (Group A), while from 1997 all patients were treated using a transperitoneal laparoscopic approach (Group B). The comparison between the 2 groups was performed considering patients characteristics, operative times, blood losses, intraoperative and post-operative complications, analgesic consumption, post-operative hospital stay and recovery. Open surgery was performed in 10 patients and laparoscopy in 13 patients. No significant difference was recorded between the two groups as to patients’ characteristics and complications. Mean operative time was significantly increased in Group B, while post-operative hospital stay was significantly longer in Group A. Laparoscopic bilateral adrenalectomy can be safely and effectively employed to treat Cushing’s syndrome. However, long operatives times may represent a limitation especially in high risk patients.

Circadian profile of serum melatonin in patients with Cushing’s syndrome or acromegaly

We evaluated the 24-h profile of serum melatonin (MT) in 16 patients with Cushing’s syndrome (11 pituitary- and 5 adrenal-dependent) aged 38.1±13.8 years and in 19 patients with acromegaly due to GH-secreting pituitary adenoma aged 52±11.9 years. Thirty-three healthy subjects aged 30±7 years and 26 healthy subjects aged 59±12 years served as age-matched controls for the two groups of patients, respectively. All the patients had active disease and were off treatment; none had overt hypopituitarism. Blood drawings were collected at 08:00, 12:00, 16:00, 20:00, 22:00, 24:00, 02:00, 04:00 and 06:00 h in controls and patients. Serum MT, cortisol, GH and IGF-I were measured by specific RIA kits and ACTH by IRMA. Cosinor rhythmometry was employed for chronobiological analysis. The acromegalic patients displayed, as a whole group, higher 24-h mean MT levels with respect to age-matched controls (M±SD: 52.9±14.6 vs 32.9±8.0 pg/ml, p<0.01) with normally synchronized MT profiles in 11/19 patients. No correlation was apparent between MT and either GH (24-h mean) or IGF-I. In the patients with Cushing’s syndrome the circadian profile of serum MT was maintained in 10/16 cases; serum MT levels were comparable to those of controls (48.8±14.0 vs 50.0±16.0 pg/ml, NS) without any difference between pituitary- and adrenal-dependent forms. No correlation was found between MT and either ACTH or cortisol levels. The present data suggest that GH hypersecretion is associated with increased MT secretion whereas hypercortisolism does not cause appreciable alterations of MT secretion.

Cushing’s syndrome due to ACTH-independent bilateral adrenocortical macronodular hyperplasia

ACTH-independent macronodular adrenocortical hyperplasia (AIMAH) is a rare cause of Cushing’s syndrome in which adrenal glands become very enlarged, occupied and distorted by multiple cortical nodules. We report on such two patients, a 44-year-old man and a 40-year-old woman. Physical examination revealed in both cases a classic cushin-goid habit. Laboratory studies showed overt hyper-cortisolism with high urinary free Cortisol excretion and elevated serum Cortisol with loss of the circadian rhythm. Serum Cortisol levels were not modified after high dose dexamethasone. ACTH levels were undetectable both in baseline conditions and following CRH or metyrapone. In both cases, abdominal CT demonstrated bilaterally enlarged adrenal glands which were distorted by multiple bumps. 131I-Nor-cholesterol scintiscan showed bilateral uptake of the radionuclide. Pituitary region was normal at neuroradiology imaging. Bilateral adrenalectomy was performed in both cases. In patient I, adrenal glands weighted 77 and 90 g, respectively, while in patient II they were of 90 and 55 g, respectively. At histological examination, the adrenal cortex was occupied by multiple nodular lesions composed mostly of clear cells. In the internodular regions, no evidence of cortical architecture was observed. At the immunohisto-chemical evaluation, both cases displayed Ki-67 staining comparable with that of ACTH-dependent diffuse hyperplasia. Postoperative course was uneventful and signs of Cushing’s syndrome resolved in about three months. At the last follow up, the patients are going well on glucocorticoid and mineralocorti-coid supplementation. Plasma ACTH levels are 65 and 107 µg/ml, respectively.