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The Glucocorticoid Receptor Is Overexpressed in Malignant Adrenocortical Tumors

Cancer Genetics Unit (L.J.T., P.S.S., B.G.R., S.B.S., R.J.C.-B.), Hormones and Cancer Group, Kolling Institute of Medical Research, University of Sydney (A.J.G.), Sydney, NSW 2006 Australia; Departments of Endocrinology (L.J.T., B.G.R., R.J.C.-B.), Anatomical Pathology (A.J.G., A.S.C., A.C.), and Endocrine and Oncology Surgery (S.B.S.), Royal North Shore Hospital, Sydney, NSW 2065 Australia; Department of Surgery (P.S.S.), Bankstown Hospital and University of New South Wales, Sydney, NSW 2052 Australia; and Departments of Genetics and Pathology (J.B.), Surgical Sciences (P.L.H.S.), and Medical Sciences (B.M.S.), University Hospital, SE-751 85 Uppsala, Sweden

Address all correspondence and requests for reprints to: Lyndal J. Tacon, Cancer Genetics Unit, Hormones and Cancer Group, Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St. Leonards, NSW 2065 Australia. E-mail: ltacon{at}med.usyd.edu.au.

Context: Adrenocortical carcinoma (ACC) is a rare tumor with a poor prognosis. The Weiss score is the most widely accepted method for distinguishing an ACC from an adrenocortical adenoma (ACA); however, in borderline cases, accurate diagnosis remains problematic. We recently discovered that the glucocorticoid receptor (GR) gene NR3C1 is significantly up-regulated in ACCs compared with ACAs in global gene expression studies.

Objective: Our objective was to study GR expression in adrenocortical tumors (ACTs) and to assess its utility as an adjunct to the Weiss score.

Design: Microarray analysis, real-time quantitative RT-PCR (qPCR), immunohistochemistry, Western blot, and direct sequencing were performed.

Results: Analysis of 28 ACTs by microarray and 49 ACTs by qPCR found NR3C1 expression to be up-regulated in ACCs compared with ACAs (P < 0.001). Western blotting and RT-PCR confirmed the presence of the GR isoform in ACCs, and no mutations were detected on direct sequencing. Immunohistochemistry for GR in an overlapping cohort of ACTs demonstrated strongly positive nuclear staining in 31 of 33 ACCs (94%), with negative staining in 40 of 41 ACAs (98%) (P < 0.001). This finding was validated in an external cohort of ACTs, such that 14 of 18 ACCs (78%) demonstrated positive nuclear staining whereas 32 of 33 ACAs (94%) were negative (P < 0.001).

Conclusions: The immunohistochemical finding of nuclear GR staining identified ACCs with high diagnostic accuracy. We propose that GR immunohistochemistry may complement the Weiss score in the diagnosis of ACC in cases that display borderline histology. The possibility that GR is transcriptionally active in these tumors, and may therefore be a therapeutic target, requires further study.