Classification Of Adrenocortical Tumors Research Articles

Nestin as a Marker in the Classification of Adrenocortical Tumors

Expression of the intermediate filament, nestin, was long believed to be restricted to neuroectodermal stem cells. However, nestin expression has recently been detected in several tumors. Since adrenocortical carcinoma, a tumor entity still very difficult to classify, may gain the ability to aberrantly express neuroectodermal proteins including chromogranin A and synaptophysin, we asked the question whether nestin might also be detected in adrenocortical carcinomas, and if so, whether it might serve as a tool for clinical pathology. Therefore, we studied the expression of nestin in normal adrenal glands, adrenocortical adenomas, and adrenocortical cancers using specific immunohistochemistry and semi-quantitative reverse transcriptase-polymerase chain reaction. Immunostaining was nestin-positive in 1 out of 9 normal adrenal glands (11%), 2 out of 20 adrenocortical adenomas (10%), and 13 out of 16 adrenocortical carcinomas (81%). Expression of nestin mRNA could be detected in all microdissected tissues, independently of their grade of dedifferentiation. We conclude that our findings provide further evidence that nestin, as a marker, is not restricted to neuronal stem cells and nestin expression is worth to be studied in adrenocortical tumors.

Molecular Classification and Prognostication of Adrenocortical Tumors by Transcriptome Profiling

Our understanding of adrenocortical carcinoma (ACC) has improved considerably, yet many unanswered questions remain. For instance, can molecular subtypes of ACC be identified? If so, what is their underlying pathogenetic basis and do they possess clinical significance? We did a whole genome gene expression study of a large cohort of adrenocortical tissues annotated with clinicopathologic data. Using Affymetrix Human Genome U133 Plus 2.0 oligonucleotide arrays, transcriptional profiles were generated for 10 normal adrenal cortices (NC), 22 adrenocortical adenomas (ACA), and 33 ACCs. The overall classification of adrenocortical tumors was recapitulated using principal component analysis of the entire data set. The NC and ACA cohorts showed little intragroup variation, whereas the ACC cohort revealed much greater variation in gene expression. A robust list of 2,875 differentially expressed genes in ACC compared with both NC and ACA was generated and used in functional enrichment analysis to find pathways and attributes of biological significance. Cluster analysis of the ACCs revealed two subtypes that reflected tumor proliferation, as measured by mitotic counts and cell cycle genes. Kaplan-Meier analysis of these ACC clusters showed a significant difference in survival (P < 0.020). Multivariate Cox modeling using stage, mitotic rate, and gene expression data as measured by the first principal component for ACC samples showed that gene expression data contains significant independent prognostic information (P < 0.017). This study lays the foundation for the molecular classification and prognostication of adrenocortical tumors and also provides a rich source of potential diagnostic and prognostic markers.

Gene Expression Profiling Reveals a New Classification of Adrenocortical Tumors and Identifies Molecular Predictors of Malignancy and Survival

Adrenocortical tumors, especially cancers, remain challenging both for their diagnosis and prognosis assessment. The aim of this article is to identify molecular predictors of malignancy and of survival. One hundred fifty-three unilateral adrenocortical tumors were studied by microarray (n = 92) or reverse transcription quantitative polymerase chain reaction (n = 148). A two-gene predictor of malignancy was built using the disease-free survival as the end point in a training cohort (n = 47), then validated in an independent validation cohort (n = 104). The best candidate genes were selected using Cox models, and the best gene combination was validated using the log-rank test. Similarly, for malignant tumors, a two-gene predictor of survival was built using the overall survival as the end point in a training cohort (n = 23), then tested in an independent validation cohort (n = 35). Unsupervised clustering analysis discriminated robustly the malignant and benign tumors, and identified two groups of malignant tumors with very different outcome. The combined expression of DLG7 and PINK1 was the best predictor of disease-free survival (log-rank P approximately 10(-12)), could overcome the uncertainties of intermediate pathological Weiss scores, and remained significant after adjustment to the Weiss score (P < 1.3 x 10(-2)). Among the malignant tumors, the combined expression of BUB1B and PINK1 was the best predictor of overall survival (P < 2 x 10(-6)), and remained significant after adjusting for MacFarlane staging (P < .005). Gene expression analysis unravels two distinct groups of adrenocortical carcinomas. The molecular predictors of malignancy and of survival are reliable and provide valuable independent information in addition to pathology and tumor staging. These original tools should provide important improvements for adrenal tumors management.

8Improvement of histopathological classification of adrenocortical tumours by genetic differentiation?

8Improvement of histopathological classification of adrenocortical tumours by genetic differentiation?

Nestin as a valuable marker in the classification of adrenocortical tumors

Nestin is a newly identified intermediate filament protein that belongs to the sixth class of intermediate filaments. Previous studies have demonstrated that nestin is abundantly expressed in neuroectodermal stem cells and is extinguished from differentiated cells of the central nervous system. Nestin is also expressed in skeletal muscle progenitor cells, but down-regulated on cellular differentiation. In addition, nestin is shown to be predominantly expressed in tumors that are thought to arise from immature cells, such as primitive neuroectodermal tumors, medulloblastomas, pediatric rhabdomyosarcomas, and gastrointestinal stromal tumors. Expression of the intermediate filament nestin was long believed to be restricted to neuroectodermal stem cells. However, expression of nestin could recently be detected in seral tumors. Since adrenocortical carcinomas, a tumor entity which is still very difficult to classify, may gain the ability to aberrantly express neuroectodermal peptides, including chromogranin A and synaptophysin, we asked whether nestin can also be detected in adrenocortical carcinomas and if so whether it is a valuable tool for the clinical pathologist. Therefore, we studied expression of nestin by normal adrenal glands, adrenocortical adenomas, and andrenocortical cancers. We found positve immunostaining in sections of 1 out of 6 normal adrenal glands (17%), 1 out of 9 adrenocortical adenomas (11%), and 10 out of 13 andrenocortical carcinomas (77%). Expression of nestin mRNA could be detected in all tissues, independently of their grade of dedifferentiation. We conclude that nestin is a valuable marker in the characterization of adrenocortical tumors. In addition, this study once more brings up the question whether nestin is specific for stem cells.

Virilising adrenocortical tumours in children

Adrenocortical tumours (ACT) are a rare but important cause of virilisation in infancy and childhood. Four cases of virilising ACT are presented. Two girls (age 0.9 years and 3.9 years) and two boys (age 6.2 years and 6.4 years) had symptoms and signs of virilisation before the age of 6 years. Diagnosis of a virilising adrenal tumour was confirmed by laboratory tests, diagnostic imaging and histology. However, one female patient was misdiagnosed and treated for 3 months as atypical congenital adrenal hyperplasia. Ultrasonography of the adrenal region could not visualise the tumour in three out of four cases. The most sensitive method of diagnostic imaging was MRI. In all cases, treatment consisted of complete surgical resection of the adrenal tumour by open abdominal surgery. Immunohistochemistry was performed in all patients and in two patients there was an overexpression of p53, indicating p53 mutation and in three cases the ki67 proliferation index was greater than 5%. The classification of ACT in childhood is extremely difficult. Histology scores adapted from adrenal tumours in adults and molecular markers are under investigation, but there is still not enough clinical experience since ACT are so rare. Long-term follow-up is mandatory not only because of the uncertainty in classification of adrenocortical tumours, but also for observation of growth and pubertal development.