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Adrenocortical carcinoma (ACC) accounts for a minority of all malignant tumors in adults. Surgery remains the most important therapeutic option for non-metastatic ACC. Whether a subset of patients with small ACC may benefit from minimally invasive surgery remains a debated issue, but we believe that surgeon’s expertise is more important than surgical technique to determine outcome. However, even a state-of-the-art surgery cannot prevent disease recurrence that is determined mainly by specific tumor characteristics. We consider that the concomitant presence of the following features characterizes a cohort of patients at low risk of recurrence, (i) R0 resection (microscopically free margin), (ii) localized disease (stage I-II ACC), and (iii) low-grade tumor (ki-67 <10%). After the ADIUVO study, we do not recommend adjuvant mitotane as a routine measure for such patients, who can be managed with active surveillance thus sparing a toxic treatment. Patients at average risk of recurrence should be treated with adjuvant mitotane. For patients at very high risk of recurrence, defined as the presence of at least one of the following: Ki67 >30%, large venous tumor thrombus, R1 resection or stage IV ACC, we increasingly recommend to combine mitotane with four cycles of platinum-based chemotherapy. However, patients at moderate-to-high risk of recurrence should be ideally enrolled in the ongoing ADIUVO2 trial. We do not use adjuvant radiotherapy of the tumor bed frequently at our institutions, and we select patients with incomplete resection, either microscopically or macroscopically, for this treatment. In the long-term, prospective multicenter trials are required to improve patient care.

Clinical endocrinologists have to deal frequently with adrenal incidentalomas in their practice. However, no comprehensive guidelines have been published by professional societies to guide assessment and management of adrenal incidentalomas and current recommendations are mainly based on the NIH state-of-the-science statement or expert opinions. An accompanying paper in this issue of the journal provides a critical revision of the relevant literature on this clinically important topic. The provocative conclusion of the authors is that current recommendations are burdened by high costs, little clinical benefit and also risk of inducing cancer. This paper has the merit to outline the limits of proposed protocols and to stimulate fruitful discussion; however, many aspects represent the personal view of the authors rather than evidence-based assumptions. The purpose of the present comment is to provide a more balanced view addressing the arguments that are condivisible and those that are based on inconsistent data. To add further to the argument of discussion, we also outline a clinically-oriented strategy for follow-up. In conclusion, the need for further research appears evident to define more efficient guidelines.

Objective: It is presently unclear whether the accuracy of midnight serum cortisol (F24) in the diagnosis of Cushing’s syndrome (CS) may be replicated under usual conditions of clinical care. The aim of the present study was to assess retrospectively the effectiveness of F24 for confirming the diagnosis in a consecutive series of 106 patients, in 78 of whom a definitive diagnosis of CS was made.

Design and methods: We have compared the results of F24, urinary free cortisol (UFC) and the overnight 1 mg dexamethasone suppression test (DST) with the definitive clinical diagnosis. Receiver operating characteristic (ROC) analysis has been performed to define the best cutoff values, the sensitivity (Se) and the specificity (Sp) of the tests.

Results: The best cutoff value for F24 was 8.3 μg/dl (Se 91.8%; Sp 96.4%). The best cutoff value for the DST was 4.0 μg/dl (Se 89.2%; Sp 90.9%). The best cutoff value for UFC was 238 μg/24 h (Se 73.2%; Sp 96.3%). The area under the curve of F24 was significantly greater than that of UFC, both in the overall series (P = 0.004) and in the subgroup of patients with mild CS (P = 0.02). The differences were analyzed by means of the two-tailed students’s t-test. With the thresholds generated by the ROC analysis, UFC would have failed to achieve the correct diagnosis in a significantly higher percentage of cases than F24 (20.4% vs 7.9%; P = 0.01). The difference was analyzed by means of the chi-squared test with Yates correction.

Conclusions: The present results show that F24 has excellent effectiveness in the diagnostic procedures for CS in stressed conditions (patients studied in a hospital ward in a nonsleeping state). The test appears to be accurate also for patients with mild hypercortisolism.

The literature on an association between acromegaly and cancer is particularly abundant on either colorectal cancer or thyroid cancer, and an endless debate is ongoing whether patients with acromegaly should be submitted to specific oncology screening and surveillance protocols. The aim of the present work is to review the most recent data on the risk of either colorectal cancer or thyroid cancer in acromegaly and discuss the opportunity for specific screening in relation to the accepted procedures in the general population.

Objective: There is scant information on the morbidity associated with subclinical Cushing’s syndrome in patients with a clinically inapparent adrenal adenoma. In the present study, we have determined the prevalence of alterations of the hypothalamic–pituitary–adrenal axis in such patients and examined whether any correlation between endocrine data and the clinical phenotype exists.

Design and methods: A multi-institutional retrospective study was carried out on 210 patients (135 women and 75 men aged 19–81 years) with an adrenal adenoma detected serendipitously between 1996 and 2000 in four referral centers in Italy.

Results: Hypertension was observed in 53.8%, obesity in 21.4% and hyperglycemia in 22.4% of patients. The 47 patients with midnight serum cortisol >5.4 μg/dl, a value corresponding to the 97th centile of 100 controls, were older and displayed greater fasting glucose (120.4±52.2 mg/dl vs 105.1±39.2 mg/dl, P = 0.04) and systolic blood pressure (148.3±14.6 mmHg vs 136.4±16.2 mmHg, P = 0.0009) than the 113 patients with normal cortisol levels. The difference in systolic blood pressure remained statistically significant (P = 0.009) when age was used as a covariate. The percentage of hypertensive patients undergoing treatment was not different between the two groups (90.5 and 97.1%) but the percentage of patients with controlled hypertension was significantly lower among the hypercortisolemic patients (12.5 vs 32.4%, P = 0.04). Glycated haemoglobin (HbA1c) levels were higher in the hypercortisolemic diabetic patients (8.9±1.1% vs 7.1±1.3%, P = 0.005).

Conclusions: Elevated midnight cortisol concentration is a reliable test to select a subgroup of patients with a clinically inapparent adrenal adenoma with an adverse cardiovascular risk profile.

Adrenocortical carcinoma (ACC) is a rare and in most cases steroid hormone-producing tumor with variable prognosis. The purpose of these guidelines is to provide clinicians with best possible evidence-based recommendations for clinical management of patients with ACC based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. We predefined four main clinical questions, which we judged as particularly important for the management of ACC patients and performed systematic literature searches: (A) What is needed to diagnose an ACC by histopathology? (B) Which are the best prognostic markers in ACC? (C) Is adjuvant therapy able to prevent recurrent disease or reduce mortality after radical resection? (D) What is the best treatment option for macroscopically incompletely resected, recurrent or metastatic disease? Other relevant questions were discussed within the group. Selected Recommendations: (i) We recommend that all patients with suspected and proven ACC are discussed in a multidisciplinary expert team meeting. (ii) We recommend that every patient with (suspected) ACC should undergo careful clinical assessment, detailed endocrine work-up to identify autonomous hormone excess and adrenal-focused imaging. (iii) We recommend that adrenal surgery for (suspected) ACC should be performed only by surgeons experienced in adrenal and oncological surgery aiming at a complete en bloc resection (including resection of oligo-metastatic disease). (iv) We suggest that all suspected ACC should be reviewed by an expert adrenal pathologist using the Weiss score and providing Ki67 index. (v) We suggest adjuvant mitotane treatment in patients after radical surgery that have a perceived high risk of recurrence (ENSAT stage III, or R1 resection, or Ki67 >10%). (vi) For advanced ACC not amenable to complete surgical resection, local therapeutic measures (e.g. radiation therapy, radiofrequency ablation, chemoembolization) are of particular value. However, we suggest against the routine use of adrenal surgery in case of widespread metastatic disease. In these patients, we recommend either mitotane monotherapy or mitotane, etoposide, doxorubicin and cisplatin depending on prognostic parameters. In selected patients with a good response, surgery may be subsequently considered. (vii) In patients with recurrent disease and a disease-free interval of at least 12 months, in whom a complete resection/ablation seems feasible, we recommend surgery or alternatively other local therapies. Furthermore, we offer detailed recommendations about the management of mitotane treatment and other supportive therapies. Finally, we suggest directions for future research.