Germline PRKACA amplification leads to Cushing syndrome caused by 3 adrenocortical pathologic phenotypes

Abstract

We describe the pathology of 5 patients with germline PRKACA copy number gain and Cushing syndrome: 4 males and 1 female, aged 2 to 43 years, including a mother and son. Imaging showed normal or slightly enlarged adrenal glands in 4 patients and a unilateral mass in the fifth. Biochemically, the patients had corticotropin-independent hypercortisolism. Four underwent bilateral adrenalectomy; unilateral adrenalectomy was performed in the patient with the adrenal mass. Pathologically, 3 patients, including the 1 with the tumor (adenoma), had primary pigmented nodular adrenocortical disease with extranodular cortical atrophy and mild intracapsular and extracapsular extension of cortical cells. The other 2 patients had cortical hyperplasia and prominent capsular and extracapsular micronodular cortical hyperplasia. Immunoperoxidase staining revealed differences for synaptophysin, inhibin-A, and Ki-67 (nuclei) in the atrophic cortices (patients 1, 2, and 3) and hyperplastic cortices (patients 4 and 5) and for Ki-67 (nuclei) and vimentin in the extracortical nodules in the 2 groups of patients. β-Catenin stained the cell membrane, cytoplasm, and nuclei of the adenoma. The patients were well at follow-up (1-23 years); 24-hour urinary cortisol excretion was elevated in the patient who had unilateral adrenalectomy.

Keywords: Adrenal; Cortical nodules; Cushing syndrome; Genetics; PRKACA.

Figure 1.

Radiologic Imaging of Adrenals (Patients 3 and 4). A, Patient 3. Coronal magnetic resonance imaging with contrast agent showed a left adrenal mass with an irregular periphery (arrow). B, Patient 4. Coronal computed tomography with contrast agent identified normal-sized adrenals (arrows) with suggestive nodularity (left gland).

Figure 2.

Left Adrenal (Patient 3). A, An intermediate-power microscopic view showed multiple, intra-adrenal cortical nodules (black asterisks) and circumscribed and uncircumscribed zones of extracapsular cortical cells (white asterisks). B, A circumscribed cortical nodule composed of eosinophilic cells with uniform nuclei was located between the atrophic cortex (above) and the medulla (below). C, A break in the capsule permitted extracapsular extrusion (circumscribed) of cortical cells (Masson trichrome) (indicated by the upper white asterisk in panel A). D, Higher-power magnification of the area indicated by the lower white asterisk in panel A showed capsular collagen fibers (stained blue) separated by cortical cells. The cells extended among the epiadrenal adipocytes, forming a circumscribed, bulbous minimass (Masson trichrome).

Figure 3.

Left Adrenal (Patient 3). A, The cortical adenoma featured a sheet of eosinophilic and clear, vacuolated cortical cells surrounded by a fibrous pseudocapsule that separated it from the attached gland, which had cortical micronodules. Small foci of extracapsular cortical cells were present (arrows). B, β-Catenin stained the cell membrane, cytoplasm, and nuclei of the tumor in panel A.

Figure 4.

Multiple Cortical Micronodules in Left Adrenal (Patient 2). The micronodules were positive for synaptophysin (B), inhibin-A (C), and melan A (D); variably positive for CD56 (E); and variably negative for vimentin (asterisks) (A). The extracortical nodule (bottom, A-F) showed zonal positive and negative staining. The atrophic cortex stained with vimentin (A), melan A (D), CD56 (E), and β-catenin (F) antibodies.

Figure 5.

Micronodules in Left Adrenal (Patient 5). The micronodules (A) were shown to be extracapsular with Masson trichrome staining (B). The micronodules were variably stained with vimentin, synaptophysin, inhibinA, melan A, CD56, and β-catenin (C, D, E, F, G, and H). The hyperplastic cortex stained strongly but variably with melan A, CD56, and β-catenin (F, G, and H), and scattered cells were stained by synaptophysin and inhibin-A antisera (D and E). M indicates medulla.