Silvia Bovio

Prevalence of adrenal incidentaloma in a contemporary computerized tomography series

Adrenal incidentalomas, defined as masses discovered incidentally during imaging investigation of non-adrenal disorders, have become a rather common finding in clinical practice. The prevalence is not well characterized and varies among studies. The aim of the present study was to perform a prospective evaluation of the prevalence of adrenal incidentalomas among subjects undergoing computerized tomography (CT) scan of the chest in a screening program of lung cancer (Tic TAC study) in Piedmont, a region of Northwestern Italy. This evaluation included 520 subjects (382 males and 138 females, aged between 55–82 yr), referred to our hospital from April to December 2001. Twenty-three patients with adrenal masses were identified: 21 adrenal adenomas, 1 myelolipoma, and 1 metastasis of lung cancer. Therefore, the overall prevalence of adrenal lesions was 4.4%, and that of benign adrenal masses was 4.2%. This prevalence is higher than those found in previous CT scan series reported in the literature, probably because of the use of high-resolution CT scanning technology. Another factor that influenced our results is that subject age is skewed towards the decades characterized by a greater occurrence of adrenal masses. The outcome of this study confirms that we are presently able to identify incidentally discovered adrenal masses more often than in early years and that the prevalence of adrenal incidentalomas on CT images is approaching that of autopsy series. The present study provides a reliable estimate of the prevalence of adrenal incidentaloma with currently used CT scanners. Notwithstanding that our subjects were at increased risk of lung cancer, the rate of adrenal metastases was low. We think that the present results can be generalized even if we may disclose the lack of histological diagnosis.

Management of adrenal incidentaloma

Clinically inapparent adrenal masses, or adrenal incidentalomas, are discovered inadvertently in the course of work-up or treatment of unrelated disorders. Cortical adenoma is the most frequent tumour detected incidentally, but adrenocortical cancer, phaeochromocytoma and metastasis are not rare. Two critical questions should be answered before trying to outline the management of adrenal incidentaloma: (1) which tumours may cause harm to the patient, and (2) can we recognize and effectively treat such tumours? Based on the available scientific evidence, two major recommendations should be made: (1) identify either primary (adrenocortical cancer) or secondary (adrenal metastasis) malignancy; (2) identify phaeochromocytoma. Radiological evaluation is the key to the differential diagnosis of benign and malignant tumours. Endocrine testing is necessary to exclude phaeochromocytoma in all patients with an adrenal incidentaloma because this tumour may remain undiagnosed after imaging studies. The management of clinically inapparent adrenal adenomas may vary depending whether or not they are functioning. It is reasonable to screen for primary aldosteronism all hypertensive patients and recommend adrenalectomy when an aldosterone-producing adenoma is confirmed. A subset of adenomas secretes cortisol autonomously and may lead to mild hypercortisolism, a condition defined as subclinical Cushings syndrome. The criteria for defining subclinical Cushings syndrome are controversial, and we currently do not have sufficient evidence to define a gold standard for screening. Also the management of this condition is largely empirical, and data are insufficient to indicate the superiority of a surgical or non-surgical approach to managing patients with subclinical Cushings syndrome.

Subclinical Cushing's syndrome

Clinically inapparent adrenal masses, or adrenal incidentalomas, are discovered inadvertently in the course of workup or treatment of unrelated disorders. Cortical adenoma is the most frequent type of adrenal incidentaloma accounting for approximately 50% of cases in surgical series and even greater shares in medical series. Incidentally discovered adrenal adenomas may secrete cortisol in an autonomous manner, that is not fully restrained by pituitary feed-back, in 5 to 20% of cases depending on study protocols and diagnostic criteria. A number of different alterations in the endocrine tests aimed to assess the function of the hypothalamic-pituitary-adrenal axis has been demonstrated in such patients. This heterogeneous condition has been termed as subclinical Cushings syndrome, a definition that is more accurate than preclinical Cushings syndrome since the evolution towards clinically overt hypercortisolism does occur rarely, if ever. The criteria for qualifying subclinical cortisol excess are controversial and we presently do not have sufficient evidence to define a gold standard for the diagnosis of subclinical Cushings syndrome. An increased frequency of hypertension, central obesity, impaired glucose tolerance, diabetes and hyperlipoproteinemia has been described in patients with subclinical Cushings syndrome; however, there is not evidence-based demonstration of its long-term complications and, consequently, the management of this condition is largely empirical. Either adrenalectomy or careful observation associated with treatment of metabolic syndrome has been suggested as treatment options because data are insufficient to indicate the superiority of a surgical or nonsurgical approach to manage patients with subclinical hyperfunctioning adrenal cortical adenomas.

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.

Screening of Cushing's syndrome in adult patients with newly diagnosed diabetes mellitus

Objective  Recent studies have shown that a relatively high number of diabetic patients may have unsuspected Cushings syndrome (CS). The aim of the present study was to screen for CS in adult patients with newly diagnosed diabetes mellitus who were not selected for clinical characteristics, such as poor control and obesity, which may increase the pre‐test probability of CS.

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.

Síndrome de Cushing subclínica

Subclinical Cushings syndrome (CS) is attracting increasing interest since the serendipitous discovery of an adrenal mass has become a rather frequent event owing to the routine use of sophisticated radiologic techniques. Cortical adenoma is the most frequent type of adrenal incidentaloma accounting for approximately 50% of cases in surgical series and even greater shares in medical series. Incidentally discovered adrenal adenomas may secrete cortisol in an autonomous manner that is not fully restrained by pituitary feedback, in 5 to 20% of cases depending on study protocols and diagnostic criteria. The criteria for qualifying subclinical cortisol excess are controversial and presently there is no consensus on a gold standard for the diagnosis of this condition. An increased frequency of hypertension, central obesity, impaired glucose tolerance, diabetes and hyperlipemia has been described in patients with subclinical CS; however, there is still no clear demonstration of the long-term complications of this condition whose management remains largely empirical. Either adrenalectomy or careful observation associated with treatment of the metabolic syndrome have been suggested as treatment options.

Cortical-Sparing Laparoscopic Adrenalectomy in a Patient with Multiple Endocrine Neoplasia Type IIA

We describe the case of a patient affected by multiple endocrine neoplasia type IIA with a new diagnosis of an asymptomatic right pheochromocytoma. The patient underwent laparoscopic adrenalectomy with adrenal sparing. The removal of the tumor was successful with preservation of about one third of the adrenal gland. At the time of the last follow-up, the patient is well with partial hypoadrenalism without replacement therapy. The limitations to cortical-sparing adrenalectomy imposed by traditional open surgery (small tumor with peripheral location) can be reconsidered using the laparoscopic approach. Laparoscopic cortical-sparing adrenalectomy should become the gold standard for treatment of bilateral pheochromocytoma. The advantages of this technique are its efficacy and its reduced invasiveness with a low rate of complications either during the operation or in the postoperative period. Moreover, the preservation of a portion of the adrenal cortex may prevent the need for a life-long steroid replacement therapy.

Pros and cons of dexamethasone suppression test for screening of subclinical Cushing’s syndrome in patients with adrenal incidentalomas

The results of dexamethasone suppression tests (DST) in the screening of subclinical hypercortisolism are not readily comparable. Aim of the present study was to review the effectiveness of overnight 1-mg DST and 8-mg DST to look for functional autonomy of clinically inapparent adrenal adenomas. Sixty-eight consecutive patients with clinically inapparent adrenal adenomas were enrolled. All patients underwent 1-mg DST. The 8-mg DST was performed in the 11 patients who had post 1-mg DST cortisol >138 nmol/l and in 11 patients who had post 1-mg DST cortisol between 50 and 138 nmol/l. The a priori probability to have autonomous cortisol secretion was defined by the presence of at least two alterations of the hypothalamic-pituitary-adrenal axis among reduced ACTH concentrations, elevated urinary free cortisol (UFC) or elevated midnight serum cortisol. Cortisol levels >138 nmol/l after the 1-mg DST increases the post-test probability of adrenal functional autonomy to 55%, whereas cortisol levels <50 nmol/l reduce the post-test probability to 8%. Cortisol levels recorded after the 8-mg DST were nonsignificantly lower than after the 1-mg DST and all the patients with cortisol >138 nmol/l after the 1-mg DST maintained cortisol above this cut-point. The 1-mg DST should be considered as the more effective test to detect autonomous cortisol secretion by a clinically inapparent adrenal adenoma when cortisol levels are >138 nmol/l, while cortisol levels <50 nmol/l reduce remarkably the post-test probability of this event. The 8-mg DST seems to replicate by large the results of the 1-mg DST

The combined low-dose dexamethasone suppression corticotropin releasing-hormone test as a tool to rule out Cushing's syndrome

OBJECTIVE It remains to be evaluated whether the combined low-dose dexamethasone suppression corticotropin-releasing hormone test (LDDST-CRH test) may add to the diagnostic approach of patients suspected to have Cushings syndrome (CS). The aim of the present study was to evaluate whether the LDDST-CRH test may have a place in the diagnostic strategy of CS. DESIGN Prospective evaluation of a consecutive series of patients with suspected CS from 2004 to 2006. METHODS All the subjects underwent the same screening protocol including 1 mg dexamethasone suppression test, 24-h urinary free cortisol (UFC), and midnight serum cortisol, followed by the LDDST-CRH test whose results were not used to establish a definitive diagnosis. Plasma dexamethasone concentration was measured 2 h after the last dose of dexamethasone. Patients qualified for CS when at least two screening tests were positive. RESULTS Sixteen patients had CS while in the remaining 15 subjects CS was excluded. Even if not statistically significant, the sensitivity and the negative predictive value of the cortisol 15 min after CRH were better than the other tests; on the other hand, the test specificity was lower. All of the patients classified as indeterminate were correctly diagnosed by the LDDST-CRH test. Nevertheless, the repeated assessment of the screening tests and the active follow-up gave the same correct results. In all of the patients misclassified by the LDDST-CRH test, the plasma dexamethasone concentrations were in the normal range. CONCLUSIONS Based on our findings, we suggest that the LDDST-CRH test may still find a place as a rule-out procedure in patients who present with indeterminate results after screening and may be unavailable to repeat testing during follow-up.