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Case Reviews

Spironolactone Bodies

An Interesting Pathological Phenomenon in Adrenal Aldosteronomas

Moore, Edwina C. MBBS, BMedSci*; Nguyen, Jane MD, PhD; Magi-Galluzzi, Cristina MD, PhD; Siperstein, Allan MD*

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doi: 10.1097/PCR.0000000000000347
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Abstract

CASE REPORT

In February 2018, a 60-year-old man was referred to the Cleveland Clinic Department of Endocrine Surgery with refractory hypertension. Laboratory testing confirmed primary hyperaldosteronism (Conn syndrome), with a plasma aldosterone of 41.9 ng/dL (3.1–35.4 ng/dL) and simultaneous direct renin measurement of 2.5 mIU/L (2.5–45.1 pg/mL). A magnetic resonance imaging scan identified a 2-cm right adrenal mass and a normal contralateral left adrenal gland. This was confirmed by selective venous catheterization under adrenocorticotropic hormone stimulation. The low inferior vena cava value for aldosterone was 159 ng/dL and for cortisol was 12.1 μg/dL (ratio 13:1). In the right adrenal vein, aldosterone was greater than 50,000 ng/dL, and cortisol was 137 μg/dL, which confirmed an appropriate step-up. In the contralateral adrenal vein, aldosterone was 3644 ng/dL, and cortisol was 133 μg/dL, which convincingly lateralized the tumor (right ratio 365:1 and left ratio 27:1).

The patient's blood pressure was poorly controlled even with 4 medications: spironolactone 50 mg/d, amlodipine 10 mg/d, losartan 100 mg/d, and clonidine 0.2 mg/ter die sumendum. In addition, he also took a daily potassium supplement. He had no other significant medical conditions. He was a nonsmoker and occasionally consumed alcohol. He had previously undergone a radical prostatectomy, but no other abdominal surgery.

On examination, he was healthy in appearance with a blood pressure of 132/80 mm Hg. His abdominal examination was unremarkable.

The patient underwent a laparoscopic right adrenalectomy via a posterior retroperitoneal approach. The procedure was uncomplicated, and he was discharged after 1 day. Although the patient still required antihypertensive medications on review 1 month later, he no longer required potassium supplementation.

The specimen was reviewed by a staff pathologist at The Robert J. Tomsich Pathology and Laboratory at the Cleveland Clinic. The final diagnosis revealed an adrenal cortical adenoma with spironolactone bodies. The gland was 2.5 × 2 × 0.6 cm and weighed 2.9 g. A 1 × 1 × 0.5-cm well-circumscribed orange nodule was present, arising from the adrenal cortex. Microscopic examination revealed a nested architecture with cortical cells displaying vacuolated eosinophilic cytoplasm. The small eosinophilic, intracytoplasmic inclusions had a laminated appearance and were consistent with spironolactone bodies.

DISCUSSION

Spironolactone bodies (S bodies) were first described by Janigan et al1 in 1963. They are solitary cytoplasmic bodies in adrenal cortical cells, unique to patients treated with spironolactone.

Spironolactone, also known as 7α-acetylthiospirolactone is a synthetic mineralocorticoid antagonist. It is commonly used to treat heart failure, essential hypertension, cirrhosis, nephrotic syndrome, and primary and secondary hyperaldosteronism. Spironolactone primarily targets the mineralocorticoid receptors in the distal convoluted tubule (where small amounts of sodium are reabsorbed) and is therefore considered a weak diuretic when administered alone. It displaces aldosterone, which decreases the absorption of sodium and water, while limiting the excretion of potassium. Its action is slightly delayed (peak effect approximately 48 hours) owing to the nuclear receptor on which it acts (Figs. 1–3).

FIGURE 1
FIGURE 1:
Gross cross section of adrenal gland with a well-circumscribed 1.0-cm yellow-tan cortical nodule.
FIGURE 2
FIGURE 2:
Hematoxylin-eosin section on low-power shows a well-circumscribed cortical nodule.
FIGURE 3
FIGURE 3:
Hematoxylin-eosin section on ×20 magnification highlights adrenal cortical adenoma, with a nested microscopic architecture. The cortical cells display vacuolated eosinophilic cytoplasm. Inset with arrow pointing at S body (laminated eosinophilic intracytoplasmic inclusions).

The incidence of adrenal S bodies in patients taking spironolactone is unknown. Earlier articles report a frequency of 74% to 100%,1 while more recently, a study in 2014 identified S bodies in only one-third of their cohort. Of note they did not identify any S bodies in patients taking the newer synthetic antimineralocorticoid, eplerenone.2

Long-term administration of spironolactone is associated with S bodies, although the pathophysiology is unclear, particularly as their target receptor is in the kidney and not the adrenal gland. One hypothesis is that they arise from the smooth endoplasmic reticulum, and their laminated appearance resembles abnormal unfolding.3,4 The presence of S bodies decreases with ongoing usage of spironolactone and eventually disappears if the medication is discontinued.5,6 The inclusions are rich in phospholipids, and the laminations contain aldosterone. S bodies have been described within both normal and abnormal adrenal tissue. The effect of dosage is unknown but not thought to be consequential.2

On macroscopic examination, cortical adenomas appear as homogeneous, tan, well-defined nodules, which are rubbery to touch. Light microscopic examination with hematoxylin-eosin stains, shows a well circumscribed, unencapsulated mass composed of nests of adrenal cortical tumor cells interspersed with bland adrenal cortical cells. S bodies appear as brightly eosinophilic inclusions of variable size (2–50 μm), surrounded by a clear halo. They vary in number per cell (from none to 20) and may be present in normal and abnormal cortical cells but are most predominant in the outer adrenal cortical layers (zona glomerulosa and upper zona fasciculata). Ultrastructurally, S bodies are composed of an electron dense core surrounded by a “scroll-like” concentric laminations of membrane.1–3,7,8 They are Luxol fast blue positive and periodic acid–Schiff negative.1,8

CONCLUSIONS

Adrenal aldosteronomas are suspected in the presence of hypertension and an adrenal mass, which may be bilateral. Selective venous catheterization of the low inferior vena cava and adrenal veins is essential to confirm the diagnosis and laterality. S bodies are pathognomonic of spironolactone treatment seen only in patients taking spironolactone with aldosteronomas.

REFERENCES

1. Janigan DT. Cytoplasmic bodies in the adrenal cortex of patients treated with spirolactone. Lancet 1963;1:850–852.
2. Patel K, Calomeni E, Nadasdy T, et al. Adrenal gland inclusions in patients treated with aldosterone antagonists (spironolactone/eplerenone): incidence, morphology and ultrastructural findings. Diagn Pathol 2014;9:147–153.
3. Kovacs K, Horvath E, Singer W. Fine structure and morphogenesis of spironolactone bodies in the zona glomerulosa of the human adrenal cortex. J Clin Pathol 1973;26:949–957.
4. Hsu S, Raine L, Martin HF. Spironolactone bodies: an immunoperoxidase study with biochemical correlation. Am J Clin Pathol 1981;75:92–95.
5. Cohn D, Jackson RV, Gordon RD. Factors affecting the frequency of occurrence of spironolactone bodies in aldosteronomas and non tumourous cortex. Pathology 1983;15:273–277.
6. Conn JW, Hinerman DL. Spironolactone-induced inhibition of aldosterone biosynthesis in primary aldosteronism: morphological and functional studies. Metabolism 1977;26:1293–1307.
7. Vacher-Lavenu MC, Lellouch-Tubiana A, Louvel A, et al. Spironolactone bodies. Light and electron microscope study apropos of 4 cases of adrenal adenomas with primary hyperaldosteronism. Ann Pathol 1982;2:311–319.
8. Aiba M, Suzuki H, Kageyama K, et al. Spironolactone bodies in aldosteronomas and in the attached adrenals. Enzyme histochemical study of 19 cases of primary aldosteronism and a case of aldosteronism due to bilateral diffuse hyperplasia of the zona glomerulosa. Am J Pathol 1981;103:404–410.
Keywords:

adrenal; endocrine; surgery

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