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Adrenocortical-Pituitary Hybrid Tumor Causing Cushing’s Syndrome

Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development (N.H., C.P.C., S.B., S.R.B.), and Laboratory of Pathology, National Cancer Institute (M.A.-A.), National Institutes of Health, Bethesda, Maryland 20892; Department of Pediatrics, Monash University (A.L.), Clayton, Victoria 3168, Australia; Division of Pediatric Endocrinology, New York University Medical Center (B.K.), New York, New York 10016; Department of Medicine and School of Biological Sciences, University of Manchester (A.W.), Manchester M13 9PT, United Kingdom; and Department of Endocrinology, University of Düsseldorf, (S.R.B.), 40225 Düsseldorf, Germany

Address all correspondence and requests for reprints to: S. R. Bornstein, M.D., Department of Endocrinology, University of Düsseldorf, Mooren Str 5, 40225 Düsseldorf, Germany. E-mail: STEFAN.BORNSTEIN{at}UNI-DUSSELDORF.DE

Abstract

We describe the first case of an adrenocortical-pituitary hybrid tumor causing Cushing’s syndrome in a 17-yr-old boy. Adrenal vein sampling confirmed elevated secretion of both cortisol and ACTH precursors from a right adrenal mass, whereas pituitary ACTH levels, as determined by bilateral inferior petrosal sinus samples (IPSS), were unresponsive to CRH and equal to peripheral levels. There was no biochemical or histological evidence for a pheochromocytoma, but, rather, the tumor demonstrated lipid-rich clear cells characteristic of an adrenocortical adenoma. Immunohistochemical analysis revealed ACTH immunoreactivity and synaptophysin proteins in the tumor. Isolation of tumor cells by the novel technique of laser capture microdissection and subsequent RT-PCR showed expression of POMC messenger ribonucleic acid and cytochrome p450 enzyme messenger ribonucleic acid within the same cells. Finally, ultrastructural analysis provided ultimate proof for adrenocortical-pituitary hybrid cells exhibiting the characteristic vesicular mitochondria and abundant smooth endoplasmic reticulum of steroid cells and the typical secretory granules of corticotrophs within the cytoplasm of the same cells. The adrenocortical tumor expressed the pituitary transcription factor pituitary homeobox factor 1 and the steroidogenic factor 1. The intermingling of the centrally located ectodermally derived pituitary tissue with the mesodermally derived adrenocortical tissue in this adenoma suggests a hitherto unrecognized genetic and phenotypic plasticity within the hypothalamic-pituitary-adrenal axis.

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