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Toxicity of adjuvant mitotane treatment is poorly known; thus, our aim was to assess prospectively the unwanted effects of adjuvant mitotane treatment and correlate the findings with mitotane concentrations. Seventeen consecutive patients who were treated with mitotane after radical resection of adrenocortical cancer (ACC) from 1999 to 2005 underwent physical examination, routine laboratory evaluation, monitoring of mitotane concentrations, and a hormonal work-up at baseline and every 3 months till ACC relapse or study end (December 2007). Mitotane toxicity was graded using NCI CTCAE criteria. All biochemical measurements were performed at our center and plasma mitotane was measured by an in-house HPLC assay. All the patients reached mitotane concentrations O14 mg/l and none of them discontinued definitively mitotane for toxicity; 14 patients maintained consistently elevated mitotane concentrations despite tapering of the drug. Side effects occurred in all patients but were manageable with palliative treatment and adjustment of hormone replacement therapy. Mitotane affected adrenal steroidogenesis with a more remarkable inhibition of cortisol and DHEAS than aldosterone. Mitotane induced either perturbation of thyroid function mimicking central hypothyroidism or, in male patients, inhibition of testosterone secretion. The discrepancy between salivary and serum cortisol, as well as between total and free testosterone, is due to the mitotane-induced increase in hormone-binding proteins which complicates interpretation of hormone measurements. A low-dose monitored regimen of mitotane is tolerable and able to maintain elevated drug concentrations in the long term. Mitotane exerts a complex effect on the endocrine system that may require multiple hormone replacement therapy.

This largest study on prognostic markers in localized ACC identified Ki67 as the single most important factor predicting recurrence in patients following R0 resection. Thus, evaluation of Ki67 indices should be introduced as standard grading in all pathology reports of patients with ACC.

A number of patients with adrenal incidentaloma are exposed to a slight degree of cortisol excess resulting from functional autonomy of the adrenal mass (usually a cortical adenoma). At present, there are only scant data on the unwanted effects of this endocrine condition referred to as subclinical Cushing's syndrome. The aim of the present study was to look for some features of the metabolic syndrome in patients with incidental adrenal adenoma. Forty-one patients (9 men and 32 women) bearing adrenal incidentaloma with typical computed tomography features of cortical adenoma were studied. For both patients and controls, exclusion criteria were age equal to 70 yr or greater, previous history of fasting hyperglycemia, or impaired glucose tolerance (IGT), severe hypertension, current use of medication or concomitant relevant illnesses, and body mass index (BMI) equal to 30 kg/m(2) or greater. Forty-one patients with euthyroid multinodular goiter accurately matched for sex, age, and BMI served for a 1:1 case-control analysis. The study design included an oral glucose tolerance test (75 g) and an endocrine workup aimed at the study of the hypothalamic-pituitary-adrenal axis. Age and BMI were fully comparable between patients (54.0 +/- 10.7 yr, 23.8 +/- 2.4 kg/m(2)) and controls (52.2 +/- 11.6 yr, 23.5 +/- 2.8 kg/m(2)). Fasting glucose and fasting insulin levels were not different between the two groups (4.96 +/- 0.61 mmol/liter vs. 4.88 +/- 0.58 mmol/liter; 67 +/- 34 pmol/liter vs. 59 +/- 32 pmol/liter), but the 2-h postchallenge glucose was significantly higher in patients than in controls (7.43 +/- 2.49 mmol/liter vs. 6.10 plus minus 1.44 mmol/liter, P = 0.01). Fifteen patients (36%) reached the World Health Organization criteria for IGT and two other patients (5%) reached those for diabetes, and 14% of the controls qualified for IGT (P = 0.01). No difference in the lipid pattern was seen between the two groups, but either systolic or diastolic blood pressure were higher in patients (135.4 +/- 15.5 mm Hg vs. 125.0 +/- 15.6 mm Hg, P = 0.003; 82.9 +/- 9.1 mm Hg vs. 75.3 +/- 6.6 mm Hg, P < 0.0001). We calculated the whole-body insulin sensitivity index derived from the oral glucose tolerance test that was significantly reduced in the patients (4.3 +/- 1.7 vs. 5.7 +/- 2.5, P = 0.01). In a multiple regression analysis, 2-h glucose was associated with BMI and midnight cortisol values (r(2) = 0.36, P = 0.002). The comparison of the patients with nonfunctioning adenoma (n = 29) with those with subclinical Cushing's syndrome (n = 12) yielded significant differences as to 2-h glucose and triglyceride levels, which were significantly higher in the second group (7.02 +/- 1.76 mmol/liter vs. 8.72 +/- 3.17 mmol/liter, P = 0.03; 1.06 +/- 0.4 mmol/liter vs. 1.73 +/- 0.96 mmol/liter, P = 0.002), but the insulin sensitivity index was conversely reduced (5.2 +/- 1.4 vs. 2.9 +/- 1.2, P < 0.0001). In conclusion, many patients with incidental adrenal adenoma display altered glucose tolerance, that may be explained by reduced insulin sens...

Context: Mitotane plasma concentrations R14 mg/l have been shown to predict tumor response and better survival in patients with advanced adrenocortical carcinoma (ACC). A correlation between mitotane concentrations and patient outcome has not been demonstrated in an adjuvant setting. Objective: To compare recurrence-free survival (RFS) in patients who reached and maintained mitotane concentrations R14 mg/l vs patients who did not. Design and setting: Retrospective analysis at six referral European centers. Patients: Patients with ACC who were radically resected between 1995 and 2009 and were treated adjuvantly with mitotane targeting concentrations of 14-20 mg/l. Main outcome measures: RFS (primary) and overall survival (secondary). Results: Of the 122 patients included, 63 patients (52%) reached and maintained during a median follow-up of 36 months the target mitotane concentrations (group 1) and 59 patients (48%) did not (group 2). ACC recurrence was observed in 22 patients of group 1 (35%) and 36 patients in group 2 (61%). In multivariable analysis, the maintenance of target mitotane concentrations was associated with a significantly prolonged RFS (hazard ratio (HR) of recurrence: 0.418, 0.22-0.79; PZ0.007), while the risk of death was not significantly altered (HR: 0.59, PZ0.20). Grades 3-4 toxicity was observed in 11 patients (9%) and was managed with temporary mitotane discontinuation. None of the patients discontinued mitotane definitively for toxicity. Conclusions: Mitotane concentrations R14 mg/l predict response to adjuvant treatment being associated with a prolonged RFS. A monitored adjuvant mitotane treatment may benefit patients after radical removal of ACC.

IntroductionAdrenocortical carcinoma is a rare tumor of the adrenal cortex which accounts for no more than 0.2% of all malignancies, with two peaks of incidence in early childhood and adults over age 60. It represents an aggressive disease with up to two thirds of cases having distant metastases at the time of diagnosis and a mean survival of less than 30 months, 1-3 although combined treatment modalities, with special reference to mitotane-based therapy, seems to improve its outcome. 4The differential diagnosis of carcinomas from adenomas has been based on several microscopic features, none of them being alone absolutely indicative of malignancy. 5,6 Despite the majority of adrenocortical carcinomas do not represent a diagnostic pitfall in the clinical practice, there are several other cases in which the distinction from their benign counterparts is not straightforward.These cases are a challenge for the pathologist, since the therapeutic strategy in adrenocortical carcinomas is radically different from that of adenomas and an accurate diagnosis is mandatory.This issue is also relevant because adrenal tumors are increasingly recognized in clinical practice:the widespread use of imaging techniques has resulted in the clinical dilemma of the adrenal incidentaloma, 7 and although the vast majority of adrenal incidentalomas are benign lesions, in up to 12% of cases an incidental adrenocortical carcinoma may be discovered. 8Different scoring systems for adrenocortical carcinoma have therefore been developed, using mathematical models or numerical scores based on the association of a given threshold for each considered parameter to malignancy. [9][10][11] The most widely employed scoring system was proposed 11 and revisited in a subsequent report 12 by Weiss, and includes nine parameters related to tumor structure (loss of clear cytoplasm, presence of diffuse architecture and of necrosis), cytological features (atypia, mitotic count, atypical mitotic figures) and invasive properties (sinusoidal, venous and capsular invasion).Unfortunately, Weiss and other scoring systems are sometimes difficult to apply, subjective and/or time consuming, despite several re-visitations and implementations occurred along years to

BACKGROUND: \ud \ud Although there is consensus that laparoscopy is the standard of care for the resection of benign adrenal tumours, there is controversy regarding the role of laparoscopy for the resection of adrenocortical cancer (ACC).\ud \ud OBJECTIVE: \ud \ud The aim of the present study was to review the ACC database of the San Luigi Hospital to compare the oncologic effectiveness of open adrenalectomy (OA) versus laparoscopic adrenalectomy (LA) in the treatment of patients with stage I and II ACC.\ud \ud DESIGN, SETTING, AND PARTICIPANTS: \ud \ud We performed a retrospective analysis involving 43 patients with stage I and II ACC who had undergone radical surgery.\ud \ud INTERVENTION: \ud \ud The patients were stratified into two groups according to the surgical procedure. The "open group" consisted of patients treated with OA; the "lap group" consisted of patients treated with LA.\ud \ud MEASUREMENTS: \ud \ud Oncologic effectiveness of the procedures was tested comparing the recurrence-free survival of patients treated with OA versus LA. Secondary outcome measures were differences in terms of type of recurrence and overall survival.\ud \ud RESULTS AND LIMITATIONS: \ud \ud The open group consisted of 25 patients and the lap group of 18 patients. The two groups were comparable in terms of demographic data. The median follow-up was 38 mo in the open group and 30 mo in the lap group. Recurrence rate was 64% in the open group and 50% in the lap group. The median recurrence-free survival was 18 mo in the open group and 23 in the lap group (p=0.8). No differences in terms of pattern of recurrences were recorded. During follow-up, 28% of the open group patients and 5% of the lap group patients died. No differences in terms of survival time were noted (p=0.3).\ud \ud CONCLUSIONS: \ud \ud The present findings provide interesting evidence that OA and LA may be comparable in terms of recurrence-free survival for patients with stage I and II ACC when the principles of surgical oncology are respected

Adrenocortical carcinoma (ACC) is a rare neoplasm characterized by poor prognosis. First-line systemic treatments in advanced disease include mitotane, either alone or in combination with chemotherapy. Studies evaluating second-line therapy options have obtained disappointing results. This trial assessed the activity and toxicity of gemcitabine plus metronomic fluoropyrimidines in heavily pretreated advanced ACC patients. From 1998 to 2008, 28 patients with advanced ACC progressing after mitotane plus one or two systemic chemotherapy lines were enrolled. They received a combination of i.v. gemcitabine (800 mg/m 2 , on days 1 and 8, every 21 days) and i.v. 5-fluorouracil protracted infusion (200 mg/m 2 /daily without interruption until progression) in the first six patients, or oral capecitabine (1500 mg/daily) in the subsequent patients. Mitotane administration was maintained in all cases. The rate of non-progressing patients after 4 months of treatment was 46.3%. A complete response was observed in 1 patient (3.5%); 1 patient (3.5%) obtained a partial regression, 11 patients (39.3%) obtained a disease stabilization and 15 patients (53.7%) progressed. Treatment was well tolerated, with grade III and IV toxicities consisting of leukopenia in six patients (21.4%), thrombocytopenia in one patient (3.5%), and mucositis in one patient (3.5%). Median time to progression and overall survival in the patient population were 5.3 (range: 1-43) and 9.8 months (range: 3-73) respectively. Gemcitabine plus metronomic fluoropyrimidines is a well-tolerated and moderately active regimen in heavily pretreated ACC patients.