ACTH-independent macronodular adrenocortical hyperplasia: immunohistochemical and in situ hybridization studies of steroidogenic enzymes.

ACTH independent bilateral macronodular adrenocortical hyperplasia (AIMAH) is associated with autonomous hypercortisolism. We report six cases of AIMAH, in which immunohistochemical studies on steroidogenic enzymes (P450scc, 3 beta HSD, P450c21, P450c17, P450c11) were performed on surgically resected adrenal glands. In situ hybridization studies of P450c17 were performed in two cases in order to localize the sites of steroidogenesis. Immunoreactivity to P450scc, P450c21, and P450c11 was observed in both clear and compact cortical cells, with compact cells displaying more intense staining, as reported in Cushing's adenoma and ACTH dependent bilateral adrenocortical hyperplasia. Immunoreactivity to P450c17 was observed predominantly in small compact cells, whereas that to 3 beta HSD occurred exclusively in clear cortical cells. In situ hybridization also demonstrated that P450c17 was localized in small compact cortical cells. This differential expression of 3 beta HSD and P450c17 in clear and compact cortical cells has been observed only in AIMAH among adrenocortical disorders. This ineffective corticosteroidogenesis may contribute to the relatively low production of cortisol. AIMAH should therefore be considered as a distinct subtype of primary adrenocortical Cushing's syndrome.