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Synaptophysin Immunoreactivity in Primary Pigmented Nodular Adrenocortical Disease: Neuroendocrine Properties of Tumors Associated with Carney Complex

The Unit on Genetics and Endocrinology, Section on Pediatric Endocrinology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health (C.A.S., L.S.K.), Bethesda, Maryland 20892-1862; Emeritus Staff, Mayo Clinic (J.A.C.), Rochester, Minnesota 55905; and the Diabetes Research Institute (H.W.), Dusseldorf; and University of Leipzig (S.B., M.E.-B., S.R.B.), 04103 Leipzig, Germany

Address all correspondence and requests for reprints to: Constantine A. Stratakis, M.D., D.Sc., Unit on Genetics and Endocrinology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 10N262, Bethesda, Maryland 20892-1862. E-mail: stratakc{at}cc1.nichd.nih.gov

Carney complex (CNC) is characterized by lentiginosis and myxomatosis together with a variety of endocrine, neural crest-derived, and other tumors, including primary pigmented nodular adrenocortical disease (PPNAD). PPNAD is characterized by lipofuscin-containing, autonomously functioning, cortisol-producing nodules surrounded by mostly atrophic adrenocortical and normal adrenomedullary tissue. The nature and origin of the tumors, including the myxomas and PPNAD, are unclear. In this study, seven paraffin-embedded PPNAD tumors, one skin myxoma, and two cell lines (one myxoma and one PPNAD) established from patients with CNC were stained with antisera for synaptophysin (SYN), neuron-specific enolase, chromogranin A, tyrosine hydroxylase, and the neural cell adhesion molecule (NCAM). In addition, one PPNAD specimen and one myxoma were analyzed by electron microscopy. The results showed that chromogranin A and tyrosine hydroxylase stained adrenomedullary tissue, but not the PPNAD nodules or the extranodular adrenal cortex. SYN, neuron-specific enolase, and NCAM also stained the medulla. PPNAD nodules and the PPNAD cell line, but not the extranodular adrenal cortex, stained intensely for SYN. The myxoma cell line, but not normal fibroblasts, stained for SYN and NCAM. Ultrastructural analysis of a PPNAD tumor and a skin myxoma revealed a well developed rough endoplasmic reticulum, prominent mitochondria, and vesicle-like structures dispersed throughout the cytoplasm. We conclude that immunostaining for SYN, a marker protein for neuroendocrine cells, clearly distinguishes PPNAD nodules from surrounding adrenocortical tissue and can be helpful in the detection of small nodules in apparently unaffected cortex. The cells of a cutaneous myxoma were also stained positive by two of the three neuroendocrine markers. Finally, both PPNAD and myxoma cells demonstrated ultrastructural features suggestive of neuroendocrine properties. These results support the previously suggested hypothesis that the genetic mechanism leading to CNC involves genes with a neuroendocrine role.

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