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Although unilateral primary aldosteronism is the most common surgically correctable cause of hypertension, no standard criteria exist to classify surgical outcomes. We aimed to create consensus criteria for clinical and biochemical outcomes and follow-up of adrenalectomy for unilateral primary aldosteronism and apply these criteria to an international cohort to analyse the frequency of remission and identify preoperative determinants of successful outcome.

CONTEXT: Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with germline mutations in TP53. According to the Chompret criteria for LFS, any patient with adrenocortical cancer (ACC), irrespective of age and family history, is at high risk for a TP53 germline mutation. However, whereas such mutations have been detected with high frequency in childhood ACC, a large cohort of adult patients with ACC has never been investigated for TP53 germline mutations. OBJECTIVE: The aim of the study was to evaluate the prevalence of TP53 germline mutations in adult patients with ACC. SUBJECTS AND METHODS: In 103 adult Caucasian patients with ACC, TP53 germline mutation analysis was performed. In patients with a TP53 germline mutation, tumor tissue was analyzed for loss of heterozygosity of TP53 and p53 immunohistochemistry. Family history and clinical course were also evaluated. RESULTS: In four patients, a total of five TP53 germline mutations were found. Two mutations occurred in exon 10 (R337H and I332M, respectively), outside the hot spot region. Here, three mutations are described for the first time in ACC, and one, which occurred combined with a second mutation (R202C) on the same allele, has never been reported before in the context of LFS. This combined mutation was associated with a remarkable family history of ACC also affecting the mother and uncle of the index patient. In the 23 patients with ACC below the age of 40 yr, 13% (95% confidence interval, 3.7–32.9%) carried a TP53 germline mutation, whereas such mutations were rare in older patients with ACC. CONCLUSION: Our findings indicate a need to revise the Chompret criteria. However, in younger adults (<40 yr old) with ACC, screening for TP53 germline mutations may be justified.

Adrenocortical carcinoma is a rare but highly malignant neoplasm with still limited treatment options. Epidermal growth factor receptor (EGFR) has been shown to be overexpressed in many solid tumors, but its expression in adrenocortical carcinoma has been studied only in a limited number of cases. Therefore, we analyzed the expression of EGFR in 169 adrenocortical carcinoma samples and compared it with 31 adrenocortical adenomas. Additionally, in 30 cases of adrenocortical carcinoma, exons 18–21 of the EGFRgene were cloned and sequenced. EGFR expression was found in 128 of 169 adrenocortical carcinoma samples (76%), and in 60 of these samples (=36%) strong membrane staining was detected. However, there was no significant correlation with clinical outcome. In addition, all 30 sequenced cases revealed unmutated EGFRgenes. In contrast, only 1 out of 31 adrenocortical adenomas weakly expressed the EGFR (3%). In summary, EGFR was overexpressed in more than three-quarters of adrenocortical carcinoma cases of this series. However, no mutations of the EGFRgene were found and EGFR expression was not of prognostic relevance. As EGFR is hardly expressed in adrenocortical adenomas, our results suggest that its expression in adrenocortical tumors indicates a malignant phenotype, which may be used in the differential diagnosis between adrenocortical adenomas and carcinomas.

Objective: Selenium (Se) in the form of selenocysteine is an essential component of the family of the detoxifying enzymes glutathione peroxidase (Gpx) and of the iodothyronine selenodeiodinases that catalyze the extrathyroidal production of tri-iodothyronine (T(3)). Thus, Se deficiency may seriously influence the generation of free radicals, the conversion of thyroxine (T(4)) to T(3) and a thyroidal autoimmune process. The aim of this study was to investigate whether serum Se levels may influence the outcome of Graves' disease (GD). Design And Methods: 83 patients (77 women, 6 men) with active GD were retrospectively analyzed (mean age 40,0 years). Twenty-four GD patients went into remission and were euthyroid during follow-up (median follow-up: 20.1 months), whereas 59 patients did not go into remission or developed relapse over the following 24 months. TSH receptor autoantibodies (TRAb) were measured using the second generation assay on the basis of human TSH receptor. Se levels were determined at the first visit in our outpatient clinic and were correlated with TRAb levels and clinical outcome of these patients. Results: Median TRAb levels in the group of remission were significantly (p &lt; 0.0001) lower than TRAb values in the relapse group (2.1 as compared to 8.6 IU/l). By comparing mean serum Se levels in the remission and relapse group no significant differences were seen (73.0 vs. 71.7 ug/l). Detailed analyses of both groups of patients, however, revealed that highest serum Se levels ( 120 ug/l) were seen in the remission group, indicating a positive effect of Se levels on the outcome of GD. In addition, we also compared these results with TRAb levels of these patients. We could show that TRAb levels and serum Se values were positively correlated in the relapse group, whereas a negative correlation of both parameters were seen in the remission group, supporting the idea of a positive effect of Se on thyroidal autoimmune process. Conclusion: Our data indicate that high serum Se levels ( 120 ug/l) may influence the outcome of GD. This is important, as Se administration trials in GD, which are under discussion need to be performed with Se supplementation at higher dosages than used in autoimmune thyroiditis.

CITED2gene deletion in mice leads to adrenal agenesis. Therefore, we analyzed CITED2, a CBP/p300 interacting transactivator with transforming activity, in the human adrenal gland. In this study, we examined CITED2 expression in human embryonic and adult adrenal glands as well as adrenocortical carcinomas. As ACTH and basic fibroblast growth factor (bFGF) are connected to the physiology and growth of adrenocortical cells we studied the regulation of CITED2 by these factors in the NCI-H295R adrenocortical carcinoma cell line. We found CITED2 expression in the adult adrenal cortex as well in adrenocortical carcinomas. At an early stage of human adrenal organogenesis CITED2 could be located to the definitive zone of the developing adrenal gland using immunohistochemistry. In NCI-H295R cells, stimulation by bFGF led to a dose-dependent increase in CITED2 promotor activity, mRNA and protein expression while ACTH had no significant effect. The stimulatory effect of bFGF could be reduced by blocking mitogen-activated protein kinase activity using the MAPkinase kinase (MEK1)-inhibitor PD98059. CITED2 is expressed in embryonic and adult human adrenal glands as well as in adrenocortical cancer. It is connected to the signaling cascades of bFGF and its expression is modulated by mitogen-activated protein kinases. This suggests a novel role for CITED2 in human adrenal growth and possibly in adrenal tumorigenesis.

Interleukin-6 (IL-6) is the end-product of a cytokine signaling cascade and is secreted by specialized immune cells during inflammation. It has a great influence on many functions, including differentiation, stimulation, and activation of immune cells, or other cells of neuroendocrine origin. Thus, IL-6 serves as a key messenger in its communication with the neuroendocrine system, and serves as a potent activator of the hypothalamic-pituitary-adrenal axis at all levels. Changes in the levels of expression of this cytokine and its receptor have been observed during chronic inflammatory disease, and have been associated with tumorigenesis. Therefore, we studied the effect of IL-6 on normal and adenomatous human adrenal cells in vitro. The expression of IL-6 receptor mRNA was quantified within the same tissue. IL-6 potently stimulated cortisol secretion from dispersed normal human adrenal cells. We found immunoreactivity for the IL-6 receptor on cultured cells and paraffin-embedded sections of adrenal tissues. Further, there was a more pronounced expression of IL-6 mRNA in adrenal adenomas of patients with Cushing's syndrome, compared to normal human adrenals. Despite this fact, the sensitivity of cells of adenomatous adrenal glands to IL-6 was significantly decreased relative to cells from normal controls. These results were confirmed employing the permanent adrenocortical cancer cell line model NCI-H295. We infer that the loss of responsivity of tumorous adrenal cells to IL-6, and in part corticotropin, is an important step in the process of adrenal tumorigenesis by which regulation by differentiating proteins is bypassed.