GLUCOCORTICOID- AND ANDROGEN-SECRETING BLACK ADRENOCORTICAL ADENOMAS: UNIQUE CAUSE OF CORTICOTROPIN-INDEPENDENT CUSHING SYNDROME
Satoshi Tanaka, MD, PhD1; Akiyo Tanabe, MD, PhD1;
Motohiko Aiba, MD, PhD2; Naomi Hizuka, MD, PhD1; Kazue Takano, MD, PhD1; Jun Zhang, MD3; William F. Young, Jr, MD, MSc4
ABSTRACT
Objective: To describe the unique association of cor- ticotropin-independent Cushing syndrome caused by corti- sol- and androgen-secreting black adrenal cortical adeno- mas with myelolipomatous change.
Methods: We report the clinical, laboratory, radio- logic, and pathologic findings from 2 patients who pre- sented with androgen excess and typical signs and symp- toms of Cushing syndrome.
Results: Endocrine investigations showed high serum cortisol concentrations that lacked diurnal rhythm, unde- tectable plasma corticotropin concentrations, and absence of serum cortisol suppression after overnight dexametha- sone suppression tests. Serum levels of adrenal androgens were elevated. Computed tomography of the abdomen revealed unilateral adrenal masses (largest lesional diam- eters 4.0 and 3.1 cm). On the basis of the plurihormonal hypersecretion and the imaging characteristics, adrenocor- tical carcinoma was considered as a possible diagnosis. However, histopathologic analysis in both patients revealed black adrenal cortical adenomas with myelolipomatous change. After surgery, adrenal androgens normalized, and
From the 1Department of Medicine, Tokyo Women’s Medical University, Tokyto, Japan; 2Department of Clinical Pathology, Tokyo Women’s Medical University Medical Center East, Tokyo, Japan; 3Department of Anatomic and Clinical Pathology, and 4Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota.
Address correspondence to Dr. William F. Young, Jr, Tyson Family Endocrinology Clinical Professor in honor of Vahab Fatourechi, Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic Rochester, 200 First St SW, Rochester, MN 55905. E-mail: young.william@mayo.edu. Copyright @ 2011 AACE.
the signs and symptoms of Cushing syndrome and andro- gen excess resolved. There was no evidence of recurrent disease at last follow-up.
Conclusions: A unique form of corticotropin-inde- pendent Cushing syndrome is described: cortisol- and androgen-secreting black adrenal cortical adenomas with myelolipomatous change. Although most patients with corticotropin-independent Cushing syndrome associated with androgen excess prove to have adrenocortical carci- noma, the clinician should be aware of the possibility of benign, black adrenal adenomas in this clinical setting. (Endocr Pract. 2011;17:e73-e78)
Abbreviations:
ACTH = corticotropin; CT = computed tomography; DHEA-S = dehydroepiandrosterone sulfate
INTRODUCTION
The causes of corticotropin (ACTH)-independent Cushing syndrome include adrenal cortical adenoma, adre- nal cortical carcinoma, primary pigmented nodular adrenal disease, micronodular unimorphic or bimorphic hyperpla- sia, and ACTH-independent macronodular adrenal hyper- plasia (1). When a unilateral adrenal mass is found in a patient with ACTH-independent Cushing syndrome, the main diagnostic considerations are adrenocortical ade- noma or adrenocortical carcinoma.
Distinguishing between adrenal carcinoma and adre- nal adenoma as the cause of Cushing syndrome is essen- tial in selecting the optimal surgical approach, assessing prognosis, and directing adjuvant therapy (2). The 2 main preoperative predictors used to distinguish adenoma from carcinoma are the adrenal hormonal profile and the imag- ing phenotype on computerized imaging. The hormonal hyperfunction associated with benign cortisol-secreting adrenal adenomas is usually limited to cortisol, whereas in patients with Cushing syndrome caused by adrenocor- tical carcinoma, in addition to cortisol hypersecretion,
these neoplasms are often associated with plurihormonal steroidogenesis (eg, hypersecretion of androgens, miner- alocorticoids, and estrogens). Thus, the steroid hormonal profile usually predicts the underlying pathology in the setting of Cushing syndrome and unilateral adrenal mass. The imaging phenotype consistent with a cortical adenoma includes small size (usually ≤3 cm in diameter); round or oval with smooth margins; homogeneous; attenuation (density) on unenhanced computed tomography (CT) of 10 Hounsfield units or less; not highly vascular; rapid washout of contrast (>50% at 10 minutes); and slow growth rate (3). The imaging phenotype consistent with an adrenocortical carcinoma includes large size (usually >5 cm in diameter); irregular shape with unclear margins; heterogeneous with cystic areas; attenuation on unenhanced CT greater than 25 Hounsfield units; usually vascular; slow washout of con- trast (<50% at 10 minutes); and rapid growth rate (3).
On gross pathologic examination, most functioning adrenal adenomas are yellow or brown; however, a small number of black adenomas have been reported (4-7). Although the black adrenal adenoma is usually nonfunc- tioning, there are isolated case reports of associated hor- monal hypersecretion. For example, adrenal black ade- nomas have been reported to hypersecrete cortisol (4,8), androgens (9), or aldosterone (9-11).
Herein, we describe 2 patients with ACTH- independent Cushing syndrome who had clinical and bio- chemical evidence of adrenal androgen excess, suggestive of adrenocortical carcinoma. However, the adrenal mass imaging phenotypes were not consistent with adrenocorti- cal carcinoma. Histopathologic and immunohistochemical analyses demonstrated that the tumors were benign, black cortical adenomas with myelolipomatous change.
CASE REPORTS
Patient 1
A 53-year-old Japanese woman with diabetes mellitus and depression had a history of gestational diabetes mel- litus diagnosed at age 38 years. After delivery, she gained 10 kg of body weight, and diabetes mellitus was diagnosed 2 years later. Although insulin therapy was initiated, gly- cemic control was not optimal. She had a cerebral stroke at age 52 years. At age 53 years, she developed signs and symptoms of Cushing syndrome (eg, moon face, central obesity, and acne).
She was 162 cm tall and weighed 68.6 kg (body mass index, 26.1 kg/m2). Her blood pressure was 130/78 mm Hg without antihypertensive medication therapy, and her pulse rate was 84 beats per minute. Signs of androgen excess and virilization included acne, facial hirsutism with dark terminal hairs, male-pattern escutcheon, deep-pitched voice, androgenic scalp hair thinning, clitoromegaly, and increased growth of terminal hairs on her extremities. The
physical examination findings were also remarkable for signs of Cushing syndrome, which included full plethoric face, central obesity, supraclavicular and dorsocervical fat pads, purple-red abdominal striae, and proximal muscle weakness.
Pertinent laboratory findings included mild renal dys- function (stage 3 chronic kidney disease), dyslipidemia, and hyperglycemia. Endocrine investigation showed high serum cortisol concentrations and suppressed plasma ACTH concentrations in the morning and lack of normal diurnal rhythm of cortisol (Table 1). The overnight 1-mg dexamethasone suppression test showed absence of corti- sol suppression. Serum levels of dehydroepiandrosterone sulfate (DHEA-S) and testosterone and urinary excretion of 17-ketosteroids were markedly elevated (Table 1). In addition, serum levels of estradiol and progesterone were elevated despite her postmenopausal state.
CT of the abdomen demonstrated a smoothly mar- ginated left adrenal mass measuring 4.0 × 3.0 × 2.5 cm in largest dimensions and an atrophic-appearing right adre- nal gland. The adrenal mass contained small high-density areas of calcification and several small low-density areas thought to represent degenerative changes (Fig. 1A). The tumor was slightly and inhomogeneously enhanced by contrast administration.
On the basis of the clinical and laboratory findings, ACTH-independent Cushing syndrome due to left adrenal neoplasm was diagnosed. After laparoscopic left adrenal- ectomy, the signs and symptoms of hypercortisolism and virilization resolved. Three months after surgery, the serum DHEA-S concentration was 9 ug/dL (reference range, 11-116 ug/dL), and the serum total testosterone concen- tration was less than 5 ng/dL (reference range, 6-82 ng/ dL). The serum cortisol concentration remained low at 1.9 ug/dL 1 year after surgery. There has been no evidence of recurrent disease 4 years postoperatively.
The tumor weighed 22.6 g and measured 4.0 x 3.5 × 2.5 cm. The sectioned surface of the tumor was black with multiple small, whitish nodules 5 mm in diameter (Fig. 1B). Microscopically, the tumor tissue mainly con- sisted of compact cells with abundant lipofuscin granules (Fig. 2A and 2B). The tumor contained small cells with an increased nuclear to cytoplasmic ratio in more than 50%; cytologically, no necrosis or mitotic activity was observed. Architecturally, the tumor showed solid nodular growth with a thin, smooth, fibrous capsule and pushing border without capsular or vascular invasion. The whitish nodules consisted of bone marrow components, such as erythro- blasts, granulocytes, megakaryocytes, and lymphocytes, and adipose tissue with lymphocytes and macrophages- findings compatible with myelolipomatous changes (Fig. 2C). The adjacent cortical tissues were atrophic (Fig. 2D). Most of the tumor cells were positive on immuno- histochemical staining for P450scc (cholesterol side-chain
| Tests | Patient 1 | Patient 2 | Reference ranges |
|---|---|---|---|
| Blood tests | |||
| Corticotropin, pg/mL | |||
| 8 AM | <5.0 | <1.0 | 10-60 |
| Cortisol, ug/dL | |||
| 8 AM | 22.8 | 17.0 | 4.0-18.3 |
| 11 PM | 19.7 | 15.0 | <5.0 |
| After 1-mg DST | 22.4 | ... | <5.0 |
| After 8-mg DST | ... | 19.0 | <1.0 |
| DHEA-S, ug/dL | 602 | ... | 11-116 |
| DHEA-S, ug/dL | ... | 356 | 44-332 |
| Total testosterone, ng/dL | 189.6 | ... | 6-82 |
| Estradiol, pg/mL | 33.9 | ... | <10 |
| Progesterone, ng/ml | 2.4 | ... | <0.9 |
| Plasma renin activity, ng/ml per h | 3.6 | 20 | 0.5-3.0 |
| Aldosterone, ng/dL | 144 | 44 | 2.2-15 |
| 24-Hour urine tests | |||
| Free cortisol, ug/24 h | 156.0 | ... | 11.2-80.3 |
| Free cortisol, ug/24 h | ... | 79.0 | 3.5-4.5 |
| 17-Hydroxycorticosteroids, mg/24 h | 9.3 | ... | 2.2-7.3 |
| 17-Ketosteroids, mg/24 h | 17.4 | ... | 2.4-11.0 |
Abbreviations: DHEA-S, dehydroepiandrosterone sulfate; DST, dexamethasone suppression test.
cleavage) and P45011ß (11-hydroxylase). In contrast, positive and negative cell areas of 3ß-hydroxysteroid dehy- drogenase staining were clearly divided in the tumor tissue.
Patient 2
A 26-year-old white woman presented with a 30-month history of progressive central obesity, secondary
amenorrhea, hypertension, scalp hair thinning, facial hir- sutism, axillary and abdominal purple-red striae, and emo- tional lability.
She was 165 cm tall and weighed 65.8 kg (body mass index, 24.2 kg/m2). Her blood pressure was 121/78 mm Hg, and heart rate was 87 beats per minute while treated with lisinopril and spironolactone. Signs of androgen
3)
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excess included acne, facial hirsutism with dark terminal hairs, male-pattern escutcheon, and androgenic scalp hair thinning. The physical examination findings were also remarkable for signs of Cushing syndrome, which included a full plethoric face, central obesity, supraclavicular and dorsocervical fat pads, and purple-red abdominal striae.
Endocrine investigation showed high serum and uri- nary cortisol levels and a suppressed plasma ACTH con- centration (Table 1). The overnight 8-mg dexamethasone suppression test showed absence of cortisol suppression. Serum DHEA-S was elevated (Table 1).
CT of the abdomen demonstrated a smoothly margin- ated right adrenal mass measuring 3.1 × 2.0 × 2.0 cm in largest dimensions and an atrophic-appearing left adrenal gland (Fig. 3A). The tumor was homogenously enhanced by contrast administration.
On the basis of the clinical and laboratory findings, ACTH-independent Cushing syndrome due to right adre- nal neoplasm was diagnosed. After laparoscopic right adre- nalectomy, the serum cortisol concentration was low at 2.3 ug/dL, the serum DHEA-S level normalized, and the signs and symptoms of hypercortisolism and androgen excess slowly resolved. Blood pressure returned to normal with- out the aid of antihypertensive medications. Serum corti- sol concentrations remained low and the patient continued to require glucocorticoid replacement at the most recent follow-up visit (4 months postoperatively).
The tumor weighed 12.4 g and measured 3.4 x 2.7 x 1.7 cm. The sectioned surface of the tumor was black (Fig. 3B). Microscopically, the tumor tissue mainly consisted of compact cells with abundant lipofuscin granules (Fig. 4A and 4B). The tumor contained small cells with an increased
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nuclear to cytoplasmic ratio in more than 50%. This soli- tary lesion architecturally showed solid nodular growth with a thin, smooth fibrous capsule and pushing border without capsular or vascular invasion. Cytologically, it lacked necrosis and mitotic activity. These findings support a diagnosis of adrenocortical adenoma instead of hyperpla- sia or carcinoma. Myelolipomatous changes were evident
(Fig. 4C). The adjacent cortical tissues were atrophic (Fig. 4D). On immunostaining, the tumor cells reacted strongly and diffusely with antibodies to melan-A and inhibin (adre- nocortical cell markers). The positive staining of these 2 markers and histopathologic findings strongly support a diagnosis of adrenocortical primary neoplasm instead of a metastatic neoplasm.
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DISCUSSION
The 2 patients described here presented with signs and symptoms of Cushing syndrome and signs of andro- gen excess. Laboratory testing documented ACTH- independent hypercortisolism and androgen excess-a combination of findings typical for adrenocortical carci- noma. However, abdominal CT revealed relatively small (4.0 cm and 3.1 cm) unilateral adrenal masses with con- tralateral adrenal atrophy. At surgery, the adrenal tumors proved to be benign, black cortical adenomas with myelo- lipomatous changes.
The association of black adrenal cortical adenomas and Cushing syndrome has been infrequently recognized in the literature (7,8) and adrenal cortical adenomas that have myelolipomatous features causing Cushing syndrome have been previously reported (12,13). However, the unique cir- cumstance of Cushing syndrome caused by a black adre- nal adenoma with myelolipomatous change, although first recognized in 2004 (14), has not been confirmed as a syn- dromic association. The additional association of adrenal androgen hypersecretion and black adrenal adenoma caus- ing Cushing syndrome has only been rarely reported (6). Because of the potential for pleurihormonal hypersecre- tion, cortisol and adrenal androgens should be measured in all patients thought to have monosecretion of one of these steroids in the setting of an adrenal mass.
Adrenal myelolipomas are usually found as isolated adrenal tumors (15) or associated with congenital adrenal hyperplasia (16,17). However, myelolipomatous changes are sometimes found in association with various adrenal tumors such as nonfunctioning adenoma (18), cortisol-pro- ducing adenoma (12,19), and aldosterone-producing ade- noma (20). We propose that the myelolipomatous changes found in these 2 patients represent a unique feature asso- ciated with cortisol- and androgen-secreting black adrenal cortical adenomas.
CONCLUSION
We report 2 cases of ACTH-independent Cushing syndrome due to cortisol- and androgen-secreting black adrenocortical adenomas with associated myelolipomatous change-an association that is more likely syndromic than coincidental.
DISCLOSURE
The authors have no multiplicity of interest to disclose.
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