Adrenocorticotropic Hormone—Independent Bilateral Adrenocortical Macronodular Hyperplasia as a Distinct Subtype of Cushing's SyndromeEnzyme Histochemical and Ultrastructural Study of Four Cases with a Review of the Literature

Abstract

Four patients with adrenocorticotropic hormone (ACTH)-independent bilateral adrenocortical macronodular hyperplasia (AIMAH) were examined. All of them were men whose ages ranged from 37 to 52 years. Plasma cortisol levels were high, with a loss of diurnal rhythmicity, and plasma ACTH was undetectable. Adrenal cortisol secretion was not suppressed by dexamethasone, but it was ACTH responsive. Test results for corticotropin-releasing hormone (CRH) also were negative. Image analyses revealed a normal sella turcica and significantly enlarged adrenal glands, which showed enhanced uptake of isotope. Both adrenal glands in all cases were between 72 and 176 g in combined weight and were composed of, and distorted by, yellow nodules. Histologically, small cortical cells with or without lipid, occasional clear cells, and rare compact cells of the usual size were increased in number in the glandular cords. Enzyme histochemically, cortical cells showed weaker activity for 3 beta hydroxysteroid dehydrogenase and other enzymes than did usual cortisol-producing adenomas. Ultrastructurally, they had moderately to poorly developed smooth endoplasmic reticulum. Nonnodular areas of the cortex consisting of nonproliferating cells were atrophic and contained no compact cell zone. This is similar to the adrenal cortices attached to cortisol-producing adenomas. These features are unique to AIMAH and suggest the presence of a distinct subtype of Cushing's syndrome.

Adrenocorticotropin‐independent macronodular adrenal hyperplasia treated by simultaneous bilateral laparoscopic adrenalectomy

“…1 Although hormonal profiles are the same as conventional Cushing's syndrome, AIMAH occurs predominantly in men and in relatively elderly individuals. Marked bilateral adrenal enlargement is characteristic.…”

“…The left adrenal gland usually is larger, with higher I 131 -adosterol uptake on scintigraphy as in the present case. 1,2,5 The adrenal cortices of AIMAH patients are occupied by nodules composed of cord-like structures and small nest-like arrangements of clear cells with abundant lipid, as well as small compact cells. In this rare disease, individual cells reportedly produce far less cortisol than cortical cells in conventional Cushing's syndrome.…”

“…Thus, a large number of cells are necessary to produce Cushing's syndrome in AIMAH, where the adrenal glands are massively enlarged. 1 The treatment of choice in AIMAH patients is bilateral adrenalectomy with subsequent steroid replacement therapy. However, the fragile nodules that largely replace normal adrenal cortex are torn easily during surgery resulting in massive hemorrhage.…”

“…Some of these represent ACTH-independent macronodular adrenal hyperplasia (AIMAH), a distinct subtype of Cushing's syndrome characterized by the largest adrenal lesions among all types of adrenocortical hyperplasia. 1,2 The treatment for AIMAH is bilateral adrenalectomy followed by corticosteroid replacement therapy. Recent reports have described simultaneous bilateral laparoscopic adrenalectomy for this disorder.…”

Cushing's syndrome secondary to ACTH-Independent macronodular adrenal hyperplasia

“…In contrast, the combined adrenal weight in patients with ACTH-dependent Cushing's disease is more modest reaching on average less than 30 g (24). The nodules are yellow in coloration, without dark pigmentation; they are composed of two types of cells, those with clear cytoplasm (lipidrich) that forms cordon-like structures and those with compact cytoplasm (lipid-poor) that forms nest or island-like structures (25,26). The status of internodu- lar cortex is controversial in AIMAH; diffuse hyperplasia is present in several cases while inter-nodular atrophy has been described in other cases (6,25,27,28) (figure 3).…”