ACTH-independent Cushing's syndrome with bilateral micronodular adrenal hyperplasia and ectopic adrenocortical adenoma

Abstract

Context: Bilateral micronodular adrenal hyperplasia and ectopic adrenocortical adenoma are two rare causes of ACTH-independent Cushing's syndrome.

Objective: The aim of the study was to evaluate a 35-yr-old woman with ACTH-independent hypercortisolism associated with both micronodular adrenal hyperplasia and ectopic pararenal adrenocortical adenoma.

Design and setting: In vivo and in vitro studies were performed in a University Hospital Department and academic research laboratories.

Intervention: Mutations of the PRKAR1A, PDE8B, and PDE11A genes were searched for in leukocytes and adrenocortical tissues. The ability of adrenal and adenoma tissues to synthesize cortisol was investigated by immunohistochemistry, quantitative PCR, and/or cell culture studies.

Main outcome measure: Detection of 17alpha-hydroxylase and 21-hydroxylase immunoreactivities, quantification of CYP11B1 mRNA in adrenal and adenoma tissues, and measurement of cortisol levels in supernatants by radioimmunological assays were the main outcomes.

Results: Histological examination of the adrenals revealed nonpigmented micronodular cortical hyperplasia associated with relative atrophy of internodular cortex. No genomic and/or somatic adrenal mutations of the PRKAR1A, PDE8B, and PDE11A genes were detected. 17alpha-Hydroxylase and 21-hydroxylase immunoreactivities as well as CYP11B1 mRNA were detected in adrenal and adenoma tissues. ACTH and dexamethasone activated cortisol secretion from adenoma cells. The stimulatory action of dexamethasone was mediated by a nongenomic effect involving the protein kinase A pathway.

Conclusion: This case suggests that unknown molecular defects can favor both micronodular adrenal hyperplasia and ectopic adrenocortical adenoma associated with Cushing's syndrome.

Figure 1

Adrenal CT scan showing normal appearance of the right adrenal gland (arrow; A) and a micronodule of the left adrenal gland (arrow; B) reaching 8 mm in diameter.

Figure 2

Macroscopic and histological presentations of the left and right adrenal glands. Macroscopic views of the left (A) and right (B) adrenals showing the left micronodule previously visualized at CT scan (arrow). C, Low magnification view (×25) showing the histological structure of the left adrenal micronodule. D, Microphotograph (×25) revealing the presence of several micronodules in the cortex of the right adrenal gland (arrows). E–H, Higher magnification views showing the presence of 17α-hydroxylase (E and F) and 21-hydroxylase (G and H) immunoreactivities in both the micronodules and the internodular cortex in the left and right adrenals (scale bar, 100 μm). G (inset), Microphotograph (×200) of a 21-hydroxylase-positive cell in the left micronodule visualized at CT scan.

Figure 3

Radiological, scintigraphic, and histological presentations of the ectopic adrenocortical adenoma. A, Abdominal CT scan showing a pararenal tumor measuring 38 mm in diameter with a spontaneous attenuation value of 28 Hounsfield units (arrow). B, Intense uptake of the tracer by the tumor at noriodocholesterol scintigraphy. C, Macroscopic view of the tumor showing multiple pigmented areas. D, Microscopic view of the tumor tissue showing two types of steroidogenic cells, i.e. large spongiocytic lipid-loaded cells (lower left field) and small compact eosinophilic cells (upper right field); magnification, ×80. E and F, Microphotographs showing the presence of 17α-hydroxylase (E) and 21-hydroxylase (F) immunoreactivities in the adenoma tissue. 17α-hydroxylase immunoreactivity was detected in both spongiocytic and compact cells, whereas 21-hydroxylase immunostaining was mainly observed in compact cells (scale bar, 50 μm).

Figure 4

Effects of synthetic glucocorticoids and ACTH on cortisol production by cultured adenoma cells. A, Effects of increasing concentrations (10⁻¹⁰ to 10⁻⁶ m) of the synthetic glucocorticoids dexamethasone (▪) and fluticasone (•) on cortisol release. B, Effect of ACTH (10⁻⁹ m) on basal cortisol secretion and actions of the GR antagonist RU486 (10⁻⁶ m) and the PKA inhibitor H89 (10⁻⁵ m) on the cortisol response to dexamethasone (10⁻⁸ m). *, P < 0.05; **, P < 0.01; ***, P < 0.0001. ns, Not significant.