Massive neonatal adrenal enlargement due to cytomegaly, persistence of the transient cortex, and hyperplasia of the permanent cortex: findings in Cushing syndrome associated with hemihypertrophy

Abstract

Described in this article is the massive enlargement of both adrenal glands in 3 newborns-2 girls and 1 boy. Two had hemihypertrophy and other congenital abnormalities but no identified genetic mutation; the third had genetically proven Beckwith-Wiedemann syndrome. Two had severe Cushing syndrome, the third had hypercortisolemia but no clinical Cushing syndrome. Bilateral adrenalectomy cured Cushing syndrome in the 2 with severe symptoms; total adrenal weight in these patients was 44 and 53 g, respectively. Unilateral adrenalectomy was performed in the third patient: the gland weighed 52 g; postoperatively, the patient's hypercortisolemia normalized, and, concomitantly, the enlarged contralateral adrenal gland had a 5-fold decrease in size with slight enlargement 6 years postoperatively. Microscopically, the 3 patients had similar pathology: massive adrenal enlargement due to a combination of cytomegaly, persistence of the transient cortex, and hyperplasia of the permanent cortex. The pathologic findings were most likely the result of the genetic mutation identified in 1 patient and of an unknown mutation in the remaining 2 patients.

Figure 1

Gross appearance of the formalin-fixed left adrenal gland (Patient 1). A, Large, round and oval, brown, tan, and grey nodules protruded from the external surface. B, The cut surface showed discrete and apparently fused tan, black, and orange-tinged nodules; some were separated by grey supporting tissue.

Figure 2

Microscopic appearance of right adrenal gland (Patient 2). A, Scanning-power image showed an irregularly shaped lesion with a barely recognizable adrenal outline; the mass was composed of large, small and ovoid nodules composed of eosinophilic cells often surrounded by a dark rim. B, In this low-power micrograph, a large core of cells with eosinophilic cytoplasm lay between a thin rim of apparently small basophilic cells (left) and a hypocellular vascular area (right) consistent with degeneration of transient cortex. C, Reticulin staining showed narrow columns of cells in the superficial cortex (permanent cortex) (left), reticulin loss deeper in the cortex (transient cortex) (center), and pericellular reticulin in the deepest area (cytomegalic area) (right). D, Intermediate-power micrograph showed some of the features present in panel B. A peripheral rim of small polygonal cells with crowded nuclei was limited by a fibrous capsule. Deep to this were larger cells with eosinophilic cytoplasm and nuclei that varied slightly in size. Still deeper were even larger cells with huge nuclei (cytomegalic cells).

Figure 3

Permanent and transient cortices (A and B from patient 2, C and D from patient 3). A, Permanent cortex beneath the capsule featured closely packed small cells with regular, hyperchromatic nuclei. These cells gradually acquired increasing amounts of eosinophilic cytoplasm, a suggestive columnar pattern, and a degree of nuclear enlargement (characteristics of transient cortex). An elongated group of cells similar to those of the permanent cortex was present in the capsule B, Permanent cortex featured round and oval microcysts with wispy content. Deeper cells had increasing amount of cytoplasm. C, Hyperplastic and hypertrophic cortex showed regular subcapsular cells that had pale, weakly eosinophilic cytoplasm and were larger than the permanent cortex-type cells. D, High-power image of cells in panel C showed weakly eosinophilic and clear cytoplasm with some cell borders visible.

Figure 4

Permanent, transient, and cytomegalic cortices (patient 2). A, Eosinophilic transient cortical cells occupied the deep portion of the cortex (center and right). The permanent cortical cells lay immediately beneath the thin capsule, which contained an oval group of permanent cortical type cells (arrow). B, Transient cortex cells with eosinophilic cytoplasm and dense nuclei varied slightly in size and were separated by dilated capillaries. C, Cytomegalic and permanent cortical-type cells in the center of the field were flanked by transient cortex cells, above left and below. D, Reticulin surrounded small groups and individual cytomegalic cells.

Figure 5

Cytomegalic cortex (patient 1). A, Huge eosinophilic cells with large to very large nuclei were juxtaposed to the permanent cortex with polymorphic cysts, without intervening transient cortex (left). B, Capillaries separated large eosinophilic cells with central and eccentric vesicular nuclei containing 1 or 2 small nucleoli. Some cells had zones of increased eosinophilia (arrows).

Figure 6

Mesenchymal mass (patient 1). A, Undifferentiated mesenchymal cells surrounding an empty cavity with papillary infoldings were flanked on both sides by adrenal cortical tissue. B, The mesenchymal cells had oval and round nuclei. The area was bordered by transient cortex cells (left). Several cytomegalic cells (arrows) were located in an area of hemorrhage.

Figure 7

Cortical hyperplasia and hypertrophy (patient 3). A, The cortex featured zones of permanent cortical cells (asterisks) that flanked an area of larger cells with partly clear cytoplasm. B, Vimentin staining emphasized the difference between the cell types in panels A. C and D, Micrographs of approximately the same cortical area as in A showed different inhibin-A and melan A staining patterns.

Figure 8

Immunostaining of permanent cortex hyperplasia (patient 2). A, Strong but patchy staining with vimentin. B, Weak staining of transient cortex (center) with synaptophysin. The adrenal medulla (right) was heavily stained. C, Strong inhibin-A staining of the transient cortex. The permanent cortex was very weakly stained. D, With melan A, there was moderately strong staining of the transient cortex (right) and weak staining of the permanent cortex (center). E, The permanent cortex showed strong staining with CD56. Extracortical permanent--type cells showed similar staining (arrows). F, B-catenin showed strong punctate and membranous staining of permanent cortex (top panel), absent punctate and reduced membranous staining of transient cortex (center panel) and no punctate or membranous staining of cytomegalic cells (bottom panel).