Diagnostic and prognostic utility of SF-1 in adrenal cortical tumours

Background and Aims: Superior imaging techniques have increased the recognition of adrenal pathology. Distinguishing benign from malignant adrenocortical tumors is not always easy. Several criteria and immunohistochemical markers have been discovered which help to differentiate between adrenocortical adenoma (ACA) and adrenocortical carcinoma (ACC). Our aim here was to evaluate the diagnostic and prognostic role of steroidogenic factor-1 (SF-1) in adult adrenocortical tumors (ACT) diagnosed using the Weiss criteria. In this cohort, we have also analyzed Ki67 and p53 expression and the extent of agreement between SF-1 and Ki-67. Methodology: This was a retrospective, observational study comprising 24 cases of adult ACT over 10 years. Immunohistochemical staining for SF-1, Ki67, and p53 was done in all the cases, and the results correlated with the morphological diagnosis made using Weiss criteria. Results: SF-1 was 100% sensitive and 80% specific as a marker of malignancy. Increased SF-1 expression correlated with worse survival. There was a moderate degree of agreement between Ki-67 labeling-index and SF-1 as a marker of malignancy with the kappa coefficient being 0.75. The sensitivity of p53 was lower than Ki67 in diagnosing ACC. Conclusion: In adult ACTs, SF-1 has diagnostic significance and prognostic implication. SF-1 is a crucial, dosage-dependent survival factor in ACC. There is a moderate extent of agreement between Ki-67 and SF-1 as a marker of malignancy.

The human adrenal cortex: growth control and disorders

This review summarizes key knowledge regarding the development, growth, and growth disorders of the adrenal cortex from a molecular perspective. The adrenal gland consists of two distinct regions: the cortex and the medulla. During embryological development and transition to the adult adrenal gland, the adrenal cortex acquires three different structural and functional zones. Significant progress has been made in understanding the signaling and molecules involved during adrenal cortex zonation. Equally significant is the knowledge obtained regarding the action of peptide factors involved in the maintenance of zonation of the adrenal cortex, such as peptides derived from proopiomelanocortin processing, adrenocorticotropin and N-terminal proopiomelanocortin. Findings regarding the development, maintenance and growth of the adrenal cortex and the molecular factors involved has improved the scientific understanding of disorders that affect adrenal cortex growth. Hypoplasia, hyperplasia and adrenocortical tumors, including adult and pediatric adrenocortical adenomas and carcinomas, are described together with findings regarding molecular and pathway alterations. Comprehensive genomic analyses of adrenocortical tumors have shown gene expression profiles associated with malignancy as well as methylation alterations and the involvement of miRNAs. These findings provide a new perspective on the diagnosis, therapeutic possibilities and prognosis of adrenocortical disorders.

Análise do perfil de expressão de microRNAs em tumores adrenocorticais benignos e malignos humanos / Analysis of MicroRNA expression profile in human benign and malignant adrenocortical tumors

Introdução: Os mecanismos moleculares que levam ao desenvolvimento de tumores do córtex suprarrenal ainda são pouco compreendidos. Uma alta frequência de carcinomas adrenocorticais na infância tem sido relatada nas regiões sul e sudeste do Brasil, com a presença de uma única mutação germinativa do supressor tumoral p53 (p.R337H) sendo evidenciada em 80- 97% dos casos. Outros fatores implicados na tumorigênese adrenocortical incluem a hiperexpressão das vias IGF2 e Wnt. Os microRNAs, fragmentos de RNA que não codificam proteínas, são capazes de controlar a transcrição gênica exercendo um papel importante no crescimento e proliferação celular. O papel dos microRNA na tumorigênese adrenal ainda não está totalmente elucidado. Objetivos: Avaliar diferenças no perfil de expressão de microRNAs entre tumores benignos e malignos do córtex da suprarrenal da população adulta e pediátrica. Comparar esta expressão entre as amostras caracterizadas pela presença da mutação germinativa p.R337H do supressor tumoral p53, hiperexpressão da via Wnt e da via do IGF2. Métodos: Trinta e seis pacientes não relacionados, adultos e crianças, foram estudados. Os pacientes tiveram avaliação do perfil de produção hormonal e das vias moleculares p53, IGF2 e Wnt. O perfil de expressão de microRNAs foi determinado utilizando-se produto comercial específico TaqMan MicroRNA Human Array (AppliedBiosystems, Forster City, CA, USA). Os dados de expressão foram analisados com o programa Expression Suite (AppliedBiosystems, Forster City, CA, USA) e Realtime Statmainer (Integromics, Granada, Espanha). O estudo de alvos e das redes gênicas afetadas foram estudados com o programa Ingenuity - IPA (Ingenuity, EUA). Resultados: A comparação do perfil de expressão entre adenomas e carcinomas revelou alteração de expressão em 89 e 21 miRNAs em adultos e crianças, respectivamente. Após a correção estatística para múltiplos testes, nove miRNAs mantiveram diferenças significantes em adultos e nenhum em...

Introduction: The molecular mechanisms that lead to the development of tumors of the adrenal cortex are still poorly understood. A high frequency of pediatric adrenocortical carcinomas has been reported in South and Southeast of Brazil, and a single germline mutation of the tumor suppressor p53 (p.R337H) has been identified in 80-97% of cases. In addition, the overexpression of IGF2 and Wnt pathways are also involved in adrenal tumorigenesis. MicroRNAs, a class of small nonconding RNA, are able to control gene transcription regulating cellular growth and proliferation. However, the role of microRNA has not been fully elucidated in adrenal tumorigenesis. Objectives: To evaluate differences in the expression profile of microRNA between adult and pediatric adrenocortical tumors. To compare microRNA expression profile among samples with and without TP53, Wnt and IGF2 abnormalities. Methods: Thirty-six unrelated patients, adults and children, were studied. Patients had comprehensive hormonal evaluation and tumor samples were studied for TP53, Wnt and IGF2. The expression profile of microRNAs were determined using specific commercial product TaqMan MicroRNA Human Array (AppliedBiosystems, Forster City, CA, USA). The expression data were analyzed with the program Expression Suite (AppliedBiosystems, Forster City, CA, USA) and Realtime Statmainer (Integromics, Granada, Spain). The study of gene networks and affected targets genes have been studied with the Ingenuity program - IPA (Ingenuity, USA). Results: Comparing expression profile between adenomas and carcinomas revealed 89 and 21 deregulated miRNAs in adults and children, respectively. After false discovery rate correction, nine microRNA have maintained significant diferences in miRNAs between adults and none in children. Among microRNAs deregulated in adults were miR-483-3p (p = 0.011), miR-1290 (p = 0.011) and miR-106b (p = 0.048). These microRNAs were selected for evaluation as biomarkers through ROC curve....

Expression of steroidogenic factor-1 and DAX-1 in human adrenocortical tumours / 中华内分泌代谢杂志

ObjectiveTo detect mRNA and protein expression of steroidogenic factor-1 ( SF-1 ) and DAX-1 in human adrenocortical tumors and normal adrenal cortex,and to investigate the effect of SF-1 and DAX-1 on the steroidogenesis and development of adrenocortical tumors.Methods Total RNA and protein was extracted from angiotensin Ⅱ unresponsive aldoterone-producing adenomas ( A Ⅱ -U-APA,n =12 ),angiotensin Ⅱ responsive aldoterone-producing adenomas ( AⅡ -R-APA,n =5 ),cortisol-producing adenomas ( CPA,n =10 ),adrenal nonfunctional adenomas ( NFA,n =10 ),aldosterone-producing carcinoma ( APC,n =2 ) and normal adrenal cortex ( NAC,n =8).To analyze gene expression of SF-1,DAX-1,ACTH receptor(ACTHR),and β-actin by real-time quantitative PCR in different tissues.The protein expression of SF-1,DAX-1,and β-actin in the same tissues by Western blot.To study the relationship of ACTHR,SF-1,and DAX-1 with clinical data in adrenocortical tumors.ResultsThe expression of SF-1,DAX-1 mRNA and protein was different in NAC,AⅡ -U-APA,A Ⅱ -R- APA,APC,CPA,and NFA tissues [ relative expression of SF-1 mRNA:24.58±2.45,23.89±3.17,21.59±3.00,(38.75,44.16),14.17±2.80,and 36.38±3.50; DAX-1 mRNA:0.57±0.06,0.37±0.05,0.43±0.05,( 1.52,1.21 ),0.39 ±0.04,and 0.83 ±0.08 ; SF-1 protein:0.76 ±0.11,0.76 ±0.10,0.73 ±0.07,(1.24,1.40),0.55±0.04,and0.98±0.10; DAX-1 protein:0.65±0.14,0.39±0.13,0.43±0.14,(1.18,1.02),0.56±0.04,and 1.03±0.13 ; all P＜0.05 or P＜0.01 ].There was negative correlation by higher SF-1/DAX-1 ratio and tumor size in AⅡ -U-APA tissues.The mRNA and protein expression of SF-1 was lower in CPA and there was the positive correlation with tumor size.Conclusion SF-1 and DAX-1 might play a key role in the development of the adrenocortical tumorigenesis and steroidogenic tissues.

Clinical Features of Adrenocortical Neoplasms

PURPOSE: Adrenocortical tumors are uncommon in children and comprise only a small proportion of primary adrenal neoplasms. The biologic behavior of these tumors may be very difficult to predict, and their rarity has hindered identification of clinical characteristics. Patients with functioning tumors have excessive steroid hormone production, and the clinical manifestation depends on the predominant hormone produced. The detection of nonfunctioning tumors is not easy and the diagnosis may be delayed. Benign tumors can be cured by complete surgical excision, but malignant cases have poor response to treatment and worse prognosis. Early diagnosis and proper management are very important because of the large proportion of functioning malignant tumors in children. We report clinical features of adrenocortical tumors in children that may be of help in the early detection, proper management, and assessment of prognosis of patients. METHODS: We reviewed the clinical characteristics of 14 cases of adrenocortical tumors, among 85 children diagnosed with adrenal tumors, who visited the Severance Hospital, College of Medicine, Yonsei University, from January 1970 to July 1996. RESULTS: 85 Patients were diagnosed with adrenal tumors. Among them, 71 cases 83.5%) were tumors of the adrenal medulla, neuroblastoma and pheochromocytoma, and 14 cases (16.5%) were adrenocortical tumors, consisting of 5 cases of adenoma, 7 cases of carcinoma, and 2 cases unspecified. The age distribution ranged from 16 months to 14 years of age, and the mean was 5 years & 11 months (median 4 years & 2 months). Sex distribution revealed a male to female ratio of 1:1.33. The left to right ratio was 3.7:1, showing a left side predominance. 13 Cases (92.9%) were functioning tumors: 12 cases (92.3%) had clinical evidence of androgen excess, among which 6 cases (46.2%) were associated with Cushing's syndrome, and 1 case was compatible with primary aldosteronism. Serum cortisol, urinary 17-ketosteroids and 17-hydroxycorticosteroids concentrations were measured in 11 cases and urinary concentrations of 17-ketosteroids were elevated in all 11 cases (100%), while 17-hydroxycorticosteroids were elevated in 4 cases (36.4%). Abnormalities of serum cortisol were found in all cases except 1: serum cortisol concentrations were abnormally elevated in 5 cases (45.5%), and the remainder (5 cases, 45.5%) showed loss of diurnal variation. Dexamethasone suppression test was performed in 9 cases, and all (100%) showed no suppression. Preoperative radiologic studies included abdominal sonograms, CT or MRI scans, and angiography. Histology showed carcinomas to be bigger and heavier than adenomas, and microscopically carcinomas had necrosis, calcifications, and invasions of vessels. Distant metastases were found in 4 cases (12.7%). Adrenalectomy with complete surgical excision was performed in 12 cases. Long-term follow-up was possible in 10 patients after operation: 3 patients initially diagnosed with adenoma survived without tumor recurrence over a year, and among 6 carcinoma patients, 4 expired within a year, and 2 survived, with one patient currently undergoing postoperative chemotherapy. Of the 10 patients currently under going follow-up, one patient was initially diagnosed with a histologically unspecified tumor, and has survived 4 years after operation. CONCLUSIONS: When adrenocortical neoplasms are suspected by clinical symptoms and laboratory findings, abdominal ultrasonogram, CT or MRI scans must be performed immediately. Early detection and proper management are important for better prognosis, but are often delayed in the majority of cases. Ultimately, pediatricians need to be familiar with clinical characteristics and laboratory findings of adrenocortical tumors, bearing in mind the possibility of diagnosis in children.