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Background The systemic inflammatory response may be associated with tumor progression. We sought to analyze the impact of neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) on recurrence-free survival (RFS) and disease-specific survival (DSS) among patients who underwent surgery for adrenocortical carcinoma (ACC).

SummaryObjective Unilateral primary aldosteronism (PA) should have a contralaterally normal and therefore suppressed adrenal zona glomerulosa. However, there is no validated definition of adrenal suppression. We created two biochemical hypotheses of adrenal suppression based upon measurements taken during adrenal vein sampling (AVS) to determine whether either proved useful for interpretation of AVS or prediction of hypertension outcome in operated cases. Design Retrospective database analysis. Patients Ninety-nine cases of PA from a tertiary hypertension unit. Measurements Hypothesis 1 was the proportional suppression of the uninvolved/lowest adrenalaldo/cortisol to IVCaldo/cortisol ratio pre- and post cosyntropin. Hypothesis 2 was the absolute decrease in the uninvolved adrenalaldo/cortisol ratio after cortrosyn injection. ROC analysis performed using lateralization and hypertension resolution as the outcomes of interest. Results Hypothesis 1 proved highly predictive of lateralization with a ROC AUC of 0·958, P

Introduction Approximately 5% of all abdominal computed tomography (CT) and magnetic resonance imaging (MRI) scans reveal an adrenal incidentaloma. Although most adrenal incidentalomas are benign non-functioning adenomas, lesions may be hormonally active and/or malignant. The aim of this study was to determine adherence to recommended international guidelines and potential influencing factors when an adrenal incidentaloma is identified in routine clinical practice. Methods A retrospective study was performed of all CT and MRI reports from December 2009 to December 2011 using a key phrase search to identify patients with an incidental adrenal lesion. Results A total of 125 patients with incidental adrenal lesions were identified, of which 74 patients were considered appropriate for further endocrine/radiological workup. Of the 74 patients, only 19 (26%) were initially referred to the endocrine service for investigation; 21/74 (28%) had complete biochemical workup and 24/74 (32%) had imaging follow-up arranged. The reporting radiologist provided advice for follow-up in 31/74 (42%), and action was more likely to be taken when this recommendation was given. Follow-up of the patients who had not received investigation was attempted resulting in assessment of a further 23 patients. Of the 44 patients who have undergone full assessment, four patients were found to have clinically significant lesions (one each of: Cushing's syndrome, phaeochromocytoma, Conn's syndrome and plasmacytoma). Conclusion This study suggests that the majority of adrenal incidentalomas may not be investigated according to current international guidelines. The recommendations by the reporting radiologist appear to influence whether a patient is referred for further investigation.

Adrenocortical tumor is a rare childhood tumor with a median age at onset of 3.2 years. Virilization is the most common sign. Laparotomy is the reference treatment and has a favorable course. The diagnosis of adrenal tumor can be difficult. The main parameters of malignant tumors are size and metastasis. Analysis of TP53 mutation can facilitate final diagnosis. We report a case of virilizing adrenal tumor that developed in a 2-month-old girl, and which was treated with laparoscopic adrenalectomy.

Aims To determine clinicopathological criteria and molecular markers helpful in distinguishing adrenocortical carcinomas (ACCs) from adrenocortical adenomas (ACAs). Methods and results We analysed retrospectively the clinical and pathological features of 50 adrenal cortical tumours, and tested the expression of miR483-3p by in-situ hybridization as well as the expression of IGF2 and Smad4 by immunohistochemistry. We found that tumour size, tumour weight, hormonal function and the Weiss system are all high-efficacy criteria for differentiating malignant from benign tumours (P

Adrenocortical carcinoma (ACC) is a relatively rare but aggressive malignancy with limited therapeutic options. Previous genome-wide expression studies have demonstrated the overexpression of interleukin-13 receptor alpha2 (IL13Rα2) in some human malignancies.The authors evaluated IL13Rα2 mRNA and protein expression in 21 normal samples, 78 benign samples, 10 primary malignant samples, and 25 metastatic/recurrent samples and performed functional analyses with IL13 ligand and IL13 Rα2 knockdown in vitro. The sensitivity of 2 ACC cell lines (NCI-H295R [high IL13Rα2 expression] and SW13 [low IL13Rα2 expression]) to a highly specific IL-13 conjugated with Pseudomonas exotoxin (IL-13-PE) also was evaluated in both in vitro and in vivo models.IL13Rα2 was overexpressed in malignant tumors compared with benign and normal samples (15-fold higher; P.05). Immunohistochemistry also confirmed higher protein expression in malignant and benign tumors than in normal adrenocortical tissues (P.05). The half-maximal inhibitory concentration for IL-13-PE was 1.3 ng/mL in the NCI-H295R cell line and 1000 ng/mL in the SW13 cell line. Mice that received intratumoral or intraperitoneal IL-13-PE injection had a significant reduction in tumor size and increased tumor necrosis compared with control groups (P.05) and also had prolonged survival (P.05). IL13Rα2 protein expression increased in cells that were treated with IL-13 ligand along with cell invasion (P.05). Direct IL13Rα2 knockdown decreased cellular proliferation and invasion (P.05).The current results indicated that IL13Rα2 is overexpressed in ACC and regulates cell invasion and proliferation. IL13Rα2 is a novel therapeutic target for the treatment of human ACC.

BACKGROUND: The authors are interested in identifying molecular markers that can aid in the diagnosis of adrenocortical carcinoma (ACC). The aim of this study was to identify microRNAs (miRNAs or miRs) that are differentially expressed in malignant adrenocortical tumors as compared with benign tumors and assess their potential as diagnostic predictors. METHODS: Differentially expressed miRNAs were identified using microarray profiling of adrenocortical tumors and validated by quantitative real-time RT-PCR. RESULTS: Microarray profiling in benign and primary malignant adrenocortical tumors revealed several significant differences between these histological groups. By using directed quantitative RT-PCR analysis on a subset of these differentially expressed miRNAs, the authors determined that miRs -100, -125b, and -195 were significantly down-regulated, whereas miR-483-5p was significantly up-regulated in malignant as compared with benign tumors. Furthermore, the current study shows that miR-483-5p expression can accurately categorize tumors as benign or malignant. CONCLUSIONS: The authors identified 4 miRNAs that are dysregulated in adrenocortical carcinoma. The high expression of one of these, miR-483-5p, appears to be a defining characteristic of adrenocortical malignancies, and can thus be used to accurately distinguish between benign and malignant adrenocortical tumors. Cancer 2011. © 2010 American Cancer Society.

Objective— To investigate the feasibility of, and outcome after, laparoscopic adrenalectomy in dogs with unilateral adrenocortical carcinoma. Study Design— Case series. Animals— Dogs (n=7) with Cushing's syndrome caused by unilateral adrenocortical carcinoma. Methods— Laparoscopic adrenalectomy with the dog in lateral recumbency on the unaffected side. Three 5-mm portals (1 laparoscopic portal, 2 instrument portals) were placed in the paralumbar fossa. A fourth instrumental portal (5–12 mm) was placed above the kidney. After dissection and hemostatic control of the phrenicoabdominal vein, the adrenal gland was carefully dissected or when there was capsule fragility, necrotic content was partially aspirated. The remaining glandular tissue was removed through the 12-mm trocar site. Results— Dogs with unilateral adrenocortical carcinoma (3 right-sided, 4 left-sided) without invasion of the caudal vena cava were successfully operated by laparoscopic approach. There were no significant intraoperative complications; 2 dogs died within 48 hours of surgery because of respiratory complications. Five dogs were discharged 72 hours after surgery, and signs of hyperadrenocorticism disappeared thereafter (survival time ranged from 7 to 25 months). Conclusions— Laparoscopic adrenalectomy is feasible in dogs with either right- or left-sided adrenocortical carcinoma not involving the caudal vena cava. Clinical Relevance— When performed by experienced surgeons, laparoscopic adrenalectomy offers a minimally invasive alternative to open laparotomy or retroperitoneal surgery for the treatment of unilateral adrenocortical carcinoma in dogs.

Summary Objective Several splice variants (SVs) of GHRH receptor (GHRH-R) have been identified in various human cancers through which GHRH antagonists may exert their IGF-II-mediated antiproliferative action. Because the overexpression of the IGF-II gene is a frequent feature of adrenal carcinoma, we searched for the presence of GHRH-R SVs in these tumours. Methods and Results The expression of GHRH-R SVs was assessed by nested PCR in 45 human adrenocortical tumours. We have amplified 720-, 566- and 335-bp PCR products only in carcinomas. Their sequence revealed three open reading frames, corresponding to SV1, SV2 and SV4 of GHRH-R. SV2 was detected in five of 24 cancers examined, whereas the incidence of SV1 and SV4 was lower. Their simultaneous expression was observed in one carcinoma. No PCR products for SV3 or wild-type GHRH-R were found in carcinomas; mRNA for wild-type GHRH-R or SVs of GHRH-R were not observed either in adenomas or in normal adrenal or in NCI-H295R cells. Interestingly, all carcinomas which expressed SVs were also positive for the presence of GHRH mRNA. Conclusion This is the first time that the expression of splice variants of GHRH-R has been demonstrated in human adrenal carcinoma. This study raises the possibility that splice variants might play a role in adrenal carcinogenesis and might offer the possibility for new therapeutic strategies at least in a subgroup of adrenal carcinomas.

Image-guided, fine-needle aspiration (FNA) cytology is performed currently in patients with malignant disease who have suspected adrenal metastases. The objective of this study was to evaluate the usefulness and safety of FNA cytology in patients with incidental adrenal masses and functioning tumors.Computed tomography (CT)-guided or ultrasound-guided aspirates using 21-23-gauge needles were performed successfully in 70 patients with functioning (n = 38 patients) and nonfunctioning (n = 32 patients) adrenal masses (median size, 4 cm; range, 3-12 cm) that were detected previously by CT scans.Definitive histology was available in 68 patients (97.1%), showing 53 benign tumors (77.9%), 11 primitive malignant tumors (16.2%), and 4 unsuspected adrenal metastases (5.9%) in patients with unknown primary tumors. In two patients with aspirate reports that ruled out malignancy, the mass was unchanged on CT scan follow-up; thus, they were considered benign lesions. The benign masses were significantly smaller (P0.01), although seven malignant tumors (46.7%) measured 3-4 cm in greatest dimension, and eight benign lesions (14.5%) measured 5-6 cm in greatest dimension. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 66.7%, 96.4%, 83.3%, 91.4%, and 90.0%, respectively, for CT scan and 93.3%, 100%, 100%, 98.2%, and 98.6%, respectively, for FNA cytology. The morbidity rate of image-guided FNA cytology was 4.3% (two patients with self-limited, asymptomatic pneumothorax and one patient with spontaneously resolved adrenal hematoma).Adrenal FNA cytology represents a safe and specific procedure for evaluating patients with adrenal masses measuring2 cm in greatest dimension. FNA is able to reveal malignancies and unsuspected pheochromocytomas and should be performed in all patients with adrenal tumors whenever requested for surgical planning.

OBJECTIVE The development and progression of sporadic adrenocortical tumours are poorly understood. In autopsy studies adrenocortical tumours are found in between 2 and 9% of the general population. In congenital adrenal hyperplasia (CAH), decreased production of cortisol leads to increased secretion of ACTH from the pituitary, resulting in hyperplasia of the adrenals. More than 95% of all cases of CAH are due to steroid 21-hydroxylase deficiency, resulting from mutations in the CYP21 gene. In subjects homozygous and heterozygous for CYP21 mutations, adrenocortical tumours have been found in a high frequency compared to the general population, suggesting that chronic ACTH stimulation may play a role in the development of this tumour form. In order to test whether mild undiagnosed CAH is a common predisposing factor, we screened 27 patients with sporadic adrenocortical tumours for CYP21 mutations. DESIGN A retrospective study. PATIENTS We screened 27 patients with sporadic adrenocortical tumours, representing both benign and malignant as well as hormonally active and silent lesions. MEASUREMENTS Mutation analyses of the CYP21 gene was performed by allele-specific PCR on high molecular weight DNA. The method used detects the nine CYP21 mutations that are responsible for 95% of all disease-causing alleles in CAH. RESULTS No mutations were detected in any of the 23 DNA samples that were prepared from leucocytes. In 4 cases where no leucocyte DNA was available, tumour tissue was analysed. In one of these tumours, two CYP21 mutations, V281 L and L307insT, were found in heterozygous form. CONCLUSION Our data indicate that mild undiagnosed congenital adrenal hyperplasia is not a common underlying factor predisposing to adrenocortical tumours, at least not in the Swedish population.

Background. The syndrome of multiple endocrine neoplasia type 1 frequently involves the adrenal cortex. The relationship between the diffuse neuroendocrine system and the adrenal cortex is not clear however, particularly as the adrenal cortex is not considered to be an intrinsic part of the diffuse neuroendocrine system. Methods. The possible relationship between the adrenal cortex and the diffuse neuroendocrine system was investigated in a study of the immunohistochemical characteristics of ten normal adrenal glands, four adrenal adenomas, and 18 adrenocortical carcinomas using the indirect peroxidase method of staining intermediate filaments and neuroendocrine proteins. Results. With synaptophysin, NSE, and vimentin there was focal staining in only few zona glomerulosa cells in the normal adrenal cortex, whereas adrenocortical carcinomas and adenomas were extensively positive for these proteins. Keratin immunoreactivity, present in 100% of the normal cortices, was demonstrable in only half of the carcinomas and absent in all adenomas. Conclusions. Adrenocortical tumors may originate from neuroendocrine foci. The findings illuminate the pathogenesis of adrenocortical carcinoma, and may carry significant implications about the choice of treatment of patients with this malignancy and other related tumors. Cancer 1995; 75:860—4.

A previously healthy 7‐year‐old male presented with hypertensive emergency, hypokalemia, and elevated plasma renin activity and aldosterone levels. There was no evidence of virilization or cushingoid features. MRI of the abdomen revealed a large (5 × 5 × 3 cm) peripherally enhancing, heterogeneous mass arising from the left adrenal gland. The patient was treated for a suspected pheochromocytoma. However, his blood pressure was not responsive to alpha‐blockade. Blood pressure was controlled with a calcium channel blocker and an angiotensin‐converting enzyme (ACE) inhibitor. A complete surgical resection of the mass was performed. Postoperatively, his blood pressure normalized and he did not require antihypertensives. On pathological examination, the tumor tissue stained negative for chromogranin and positive for renin. The final diagnosis was renin‐secreting adrenal corticoadenoma, an extremely rare adrenal tumor not previously reported in a pediatric patient. Malignant hypertension due to a renin‐secreting tumor may need to be distinguished from a pheochromocytoma if alpha‐adrenergic blockade is ineffective.

Background. The case of a benign oncocytoma arising in a patient from retroperitoneal heterotopic adrenocortical tissue is reported; this tumor was found in a 44-year-old man. Methods. The tumor consisted of polygonal cells with granular eosinophilic cytoplasm packed with swollen mitochondria. Results. Scattered tumor cells showed abundant smooth endoplasmic reticulum suggesting that the tumor was of adrenocortical origin. Cancer 1992; 70:2681-4

Cushing syndrome in pregnancy is rare. This is explained by the syndrome's association with amenorrhoea, oligomenorrhoea, infertility and abortions. Cushing syndrome commonly presents with hypertension, weight gain, diabetes, striae or truncal obesity, all of which can be consistent with pregnancy in women without Cushing syndrome. We describe a case of Cushing syndrome in pregnancy secondary to an adrenal cortical tumour which was discovered after an abnormal glucose tolerance test. The woman developed classical features of Cushing syndrome including gestational diabetes and hypertension and was managed successfully to term after a unilateral adrenalectomy at 23 weeks. The case is reported not only because of its rarity but also because the diagnosis was made after a routine screening test for gestational diabetes. Early diagnosis and treatment of adrenal adenoma causing Cushing syndrome in pregnancy reduces maternal and fetal morbidity and mortality.

A case of recurrent and metastatic nonfunctioning adrenocortical carcinoma in a 40-year-old woman is reported. The patient received 4 laparotomies and 1 thoracotomy for recurrent and metastatic disease after removal of the primary adrenal tumor. She has been alive for over 18 years following multiple surgery for diseases after the first adrenalectomy. In selected patients with recurrence and/or metastasis, repeated surgical resection offers the possibility of a cure or extended palliation.

Pediatric adrenal tumors, other than neuroblastoma, are rare and can be associated with a genetic predisposition. In this report we describe two patients with an isolated and apparently sporadic adrenocortical tumor; one girl with a carcinoma, the other girl with an adenoma. In both patients genetic screening revealed hypomethylation of the KCNQ1OT1 gene, well-known for its association with the Beckwith-Wiedemann syndrome. This represents a likely novel genetic predisposition in patients with adrenocortical tumors without clear phenotypic features of the Beckwith-Wiedemann syndrome.

The association between idiopathic inflammatory myositis and cancer is well recognized. Most descriptions have been of dermatomyositis-associated cancer, however, a few have been of polymyositis-associated adrenal cancer. Here, we report a 69-year-old man in whom polymyositis-associated adrenal cancer was diagnosed. The patient complained of difficulty with walking and with standing unassisted. Physical examination and electrophysiological studies revealed an abnormality of the proximal muscles. Serum levels of creatine kinase and lactic dehydrogenase were increased. Imaging studies showed a solid tumor measuring 14 x 9 cm in the retroperitoneum. After surgical excision of the tumor, including the left kidney, the serum levels of creatine kinase and lactic dehydrogenase normalized, and symptoms of myositis disappeared.

The production of collagen fibrils, especially collagen type III, was studied with regard to eight adrenocortical adenomas with Cushing's syndrome. Anti-type III procollagen amino-terminal peptide serum (procollagen III) was employed for the PAP method. In areas of clear-type cells, the parenchymal cells were negative for procollagen III, but the stroma exhibited an intense reactivity and were arranged in an alveolar fashion. On the other hand, it was obvious that not only interstitial cells or spindle-shaped cells but also the parenchymal cells synthesized procollagen III in areas of compact-type cells, and the stroma showed a strongly positive reaction to it.