CASE REPORT

Adrenogenital Syndrome Caused by anAndrogen-Producing Adrenocortical Tumor

T

oshikoSakuma, Torn Yamaguchi, Hiromi Abe, Fumio Kanda, Keisuke Hanioka*,

Katsuya Hisano**, Hiroshi Ito***, Masayoshi Okada** and Kazuo Chihara

We describe here a typical case of virilizing adrenocortical tumor. A 23-year-old Japanesewoman had her male-like musculature, hirsutism, the absence of breast development and markedclitoromegaly. Adrenal androgens were remarkably elevated, with plasma dehydroepiandrosteronesulfate 2,752 Jig/dl, plasma testosterone 250 ng/dl and urinary 17-ketosteroids 203.4 mg/day. Awell-encapsulated tumor approximately 7 cm in diameter was detected in the left adrenal gland bycomputed tomography, magnetic resonance imaging and arteriography. The tumor was surgicallyresected and histologically diagnosed as a benign adrenocortical adenoma. The elevated adrenalandrogens returned to normal postoperatively with amelioration of her masculinized clinical

features.(Internal Medicine 33: 790-794, 1994)

Key words: virilization, hirsutism, adrenal gland, dehydroepiandrosterone, testosterone

Introduction

The vast majority of cases offemale pseudohermaphroditismreported in Japan are caused by congenital adrenal hyperplasia,

but a small percentage (3.6%) are caused by an androgen-producing adrenal tumor (1). Seventy-five percent of such

tumors are malignant (2), and thus a benign virilizing adrenaltumoris rather unusual. We describe here a typical case ofvirilizing adrenocortical tumor without apparent histologicalevidence of malignancy.

Case Report

A 23-year-old Japanese womenwasadmitted to our hospitalin April 1993, with the complaint of the absence of breastdevelopment. The patient's menstrual cycle had been irregularsince menarche at age 1 1. She began to notice the appearanceof a deep voice and the presence of excess body hair at age 12,as well as the growing of a sparse beard at age 14. The beardgradually became heavy and necessitated shaving every day at

age20.On physical examination the patient showed male-like mus-

culature with undeveloped breasts (Fig. 1A). Her blood pres-sure was 106/60 mmHg. A fist-sized elastic soft mass was

palpable in the left subcostal region of the abdomen. Agynecological examination revealed marked enlargement ofthe clitoris (Fig. IB), ovarium of normal size and slightlyatropic uterus. The peripheral blood count and blood chemistrywereall normal. The patient had a normal 46, XX karyotype.

Endocrinological studies revealed that adrenal androgenswere remarkably elevated, with plasma dehydroepiandrosterone(DHEA) 17,000 ng/dl (normal range 212-803 ng/dl), plasma

dehydroepiandrosterone sulfate (DHEA-S) 2,752 jag/dl (nor-mal range 72-325 jag/dl), plasma androsterone 6.72 ng/ml

(normal range 0. 14-1.03 ng/ml), plasma testosterone 250 ng/dl(normal range 10-90 ng/ml) and urinary 17-ketosteroids (17-KS) 203.4 mg/day (normal range 2.4-1 1.3 mg/day). In contrast,

glucocorticoid levels were all normal, with plasma ll-deoxycortisol 0.18 ng/ml (normal range 0.04-1.16 ng/ml),

plasma cortisol 10.7 jag/dl (normal range 6.4-18.5 jag/dl) andurinary 17-hydroxycorticoids ( 17-OHCS) 6.7 mg/day (normalrange 1.6-8.8 mg/day). Concerning levels of the mineralo-corticoids, plasma deoxycorticosterone (0. 17 ng/ml; normalrange 0.08-0.28 ng/ml) and corticosterone (6.38 ng/ml/h; nor-mal range 0.38-8.42 ng/ml) were normal. Plasma renin activity(4.6 ng/ml/h; normal range 0.3-2.9 ng/ml/h) and plasma aldos-

terone (273 pg/ml; normal range 56.9-150.3 pg/ml) weremoderately elevated. Both values were elevated to 1 8 ng/ml/h

F

romthe Third Division, Department of Medicine, *the Department of Pathology, * *the Second Department of Surgery and ***the First Department of Pathology,Kobe University School of Medicine, Kobe

Received for publication March 7, 1994; Accepted for publication August 12, 1994

R

eprint requests should be addressed to Dr. Tom Yamaguchi, the Third Division, Department of Medicine, Kobe University School of Medicine, 7-5- 1 , Kusunoki-cho, Chuo-ku, Kobe 650

790 Internal MedicineVol. 33, No. 12 (December 1994)

Virilizing Adrenocortical Tumor

Fig.1. A) A 23-year-old female with a virilizing

a

drenocortical tumor. Note her male-like musculature and theabsence of breast development. B) Appearance of external geni-talia with marked enlargement of the clitoris.

T

able1. Effect of Dexamethasone Ingestion on Plasma Cortisol,DHEA-Sand Urinary 17-KS Levels (Dexamethasone Sup-pression Test)

Dexamethasone dose*

None 2mg/day 8mg/day

Plasma cortisol (jLLg/dl) 1 1. 1 1. 1 1.0

Plasma DHEA-S (jig/dl) 2,329 1 ,9 1 8 1 ,476

Urinary 17-KS (mg/day) 261.5 203.6 225.4

*Oral administration of dexamethasone at 2 mg/day or 8 mg/daycaused a significant suppression of plasma cortisol, but did notsignificantly

suppress plasma DHEA-S or urinary KS.

Table2. Orcadian Rhythm ofPlasmaACTH and CortisolLevels

Time 9:00 16:00 23:00

Cortisol (jig/dl) 6. 1 5.9 1.4

ACTH (pg/ml) 16.5 14.1 7. 1

The circadian rhythms of plasma ACTH and cortisollevelswere normal, showing declines during a nocturnal

period.

and 459 pg/ml, respectively, by the combined stimulation ofcompulsive intravascular dehydration by an intravenous injec-tion of 40 mg furosemide and 2 hours upright standing.Dexamethasone failed to suppress plasma DHEA-S or urinary17-KS at doses of 2 and 8 mg/day, whereas it strongly sup-pressed plasma cortisol at both concentrations (Table 1). Thecircadian rhythms of plasma adrenocorticotropic hormone(ACTH) and cortisol were preserved, as shown by declines in

t

heir levels during a nocturnal period (Table 2).An abdominal computed tomographic (CT) scan revealed a

round tumor of approximately 7 cm in diameter in the leftadrenal region. Low density areas were visible inside the tumor(Fig. 2A). Magnetic resonance imaging (MRI) of the tumorexhibited a slightly low signal on a T{-weighted image and ahigh signal on a T2-weighted image (Fig. 2B). Adrenalscintigraphy with 13 1I-adosterol revealed a diffuse uptake of the

radioactive agent by the tumor. The right adrenal gland alsostrongly uptook the agent and was thought to have a normalfunction (Fig. 2C). Abdominal arteriography demonstrated thatthe tumor was fed by the left upper adrenal artery, confirmingthe adrenal origin of the tumor (Fig. 2D).

On the basis of the clinical features as well as the

endocrinological and radiological findings, a left virilizingadrenocortical tumor was diagnosed and surgically resected inMay 1993. The tumor was well-encapsulated without any

invasion of the surrounding tissue, and easily removed from theabdominallumen. The resected tumor was yellowish brown,8x8x4 cmlarge and weighed 400 g. Its cut surface containedareas ofnecrosis and hemorrhage (Fig. 3A). Histologically, thecells were compact and predominantly eosinophilic with ovoidvesicularnuclei, and were arranged in either a trabecular patternorsolid sheets. Neither extension beyond the adrenal capsulenor mitotic figures of the nuclei were observed microscopically,being compatible with the diagnosis of a benign adrenocorticaladenoma (Figs. 3B and C). One month after surgery, adrenalandrogens became normal, with DHEA 258 ng/dl, DHEA-S158 jag/dl, androsterone 0.2 ng/ml, testosterone 10 ng/dl andurinary 17-KS 4.7 mg/day. The patient began to notice thedisappearance of hirsutism 3 months after the operation. Nei-

ther re-elevation of adrenal androgens nor recurrence of thetumor on CT films has been observed during 9 months' follow-up at our outpatient clinic.

Discussion

Adrenal tumors are usually categorized as either benign ormalignant or as either functional or nonfunctional. An adrenal

mass has been discovered incidentally in at least 2% ofpatients, through the recent expansion of the application of CTin upper abdominal examinations (3). A recent, large-scalesurvey of 210 cases of incidental adrenal tumors conducted inJapan (4) revealed that the most common diagnosis was

Internal MedicineVol. 33, No. 12 (December 1994) 791

Sakuma et al

Fig. 2. Abdominal CT A) and T2-weighted MRI B) reveal a round tumor about 7 cm in diameter with inner low attenuation in theleft adrenal region. C) Adrenal scintigraphy with 1 3 1I-adosterol reveals the diffuse uptake of the agent by the tumor, as well as by the rightadrenal gland. D) Selective angiography of the left adrenal artery reveals tumor vessels and tumor stain.

nonfunctioning cortical adenoma (69 cases), followed bypheochromocytoma (49 cases). A total of 14 malignant tumors

(6.7%) and 16 functioning benign cortical lesions were alsofound.However, no virilizing adrenal tumor was found in thissurvey, indicating its rare incidence. Another literature searchby Shimazaki et al (5) found that 374 cases of adrenocorticaltumors were reported in Japan through 1993, and that 68 of thetumors (1 8%) resulted in virilization. Virilizing adrenal tumorspredominantly occur in childhood, as 51 of the above cases

(75%) occurred at age 10 or less.

The present case is thought to have the typical clinicalfeatures of a virilizing adrenocortical tumor, in terms of thephysical, hormonal and radiological findings. The hormonal

study showed that neither plasma DHEA-S nor urinary 17-KSwere suppressed by dexamethasone, suggesting autonomoussecretions of adrenal androgens from the tumor. The pathologi-

cal findings of the resected specimen confirmed the adrenalorigin of the tumor, and plasma adrenal androgens and their

metabolites in the urine returned to normal after surgery,indicating that the tumor itself clearly secreted adrenal andro-gens to the circulating blood, thereby causing virilization in this

patient.Virilizing adrenal tumors are known to be associated with

high levels of both plasma DHEA and DHEA-S in almost allcases, whereas plasma glucocorticoids and their urinary

metabolite,17-OHCS, are not always elevated but are fre-

792 InternalMedicineVol. 33, No. 12 (December 1994)

Virilizing Adrenocortical Tumor

Fig. 3. A) Cut surface of the adrenal tumor containing areas of necrosis and hemorrhage. B, C)Microscopic appearance of the adrenal tumor (HE stain, x40 and x l 20, respectively).

quently normal (5). This is because virilizing adrenal tumorstend to have normal or diminished activities of the enzymes 3B-hydroxysteroid dehydrogenase-isomerase, 2 1 -hydroxylase and

1 1-hydroxylase (6-8). All of these enzymes are indispensablefor the syntheses of glucocorticoids, but not for the syntheses ofDHEA or DHEA-S in the adrenal gland. Therefore, only

approximately one-fourth of virilizing adrenocortical tumors

have been reported to secrete sufficient levels ofglucocorticoidsinto the circulating blood to induce Cushing's syndrome (5).Contrary to the typical elevation of plasma levels of both DHEAand DHEA-S in the present patient, neither clinical features norhormonal abnormalities characteristic of glucocorticoid excess

were found: both basal levels and circadian rhythms of plasmaACTHand cortisol were normal, and plasma cortisol levelswere suppressed by a small dose of dexamethasone, indicating

a

normal ACTH-glucocorticoid axis.In the present case, the plasma aldosterone level was mod-

erately elevated. Since neither plasma deoxycorticosterone norcorticosterone, both aldosterone precursors, increased, it is

unlikely that the high aldosterone level was due to excessproduction by the tumor itself. Elevated plasma renin activity(PRA) was probably responsible for this high aldosterone levelin the patient, since a dependency of aldosterone secretion onPRA was demonstrated by the test of compulsive intravascular

InternalMedicineVol. 33, No. 12 (December 1994) 793

Sakumaet al

dehydration.Seventy-five percent of virilizing adrenocortical tumors

reported in Japan were malignant according to a literaturesearch from 1968 to 1986 by Nakagawa et al (2). Preoperativeevaluation of the nature of the adrenal mass is important, sincethe prognosis of malignant adrenocortical tumors is poor, withoverall median and five-year survival rates of 14 months and24%, respectively (9). In general, early and complete demon-stration of tumor involvement by imaging modalities, such asCT, MRI and arteriography, allows accurate assessment of

tumor extension and subsequent complete surgical removal(10, 1 1). When a tumor is apparently confined to the adrenalgland without any dissemination to other organs, the criterionofa mass larger than 6 cm is considered to be the most positivepredictor of malignancy (3). Copeland (8) reported that adenomaslarger than 6 cm in diameter were rare (3 in 12,000 autopsies),whereas most adrenocortical carcinomas (105 of 1 14) wereover 6 cm in diameter. However, the size of an adrenal mass asan indicator of malignancy or benign status is still the subject of

c

ontroversy (12, 13). Fishman et al (14) have recently reported

that the size of adrenocortical carcinomas tended to be smallerthan6 cm in diameter on CT, contrary to the establishedconcepts. The presence of calcification and low density areaswithin the mass also have been proposed as characteristics ofadrenocortical carcinomas on CT ( 15), but these characteristics

can be seen in both benign and malignant tumors, and thus areof little help in the discriminating process (13, 14). Abiochemi-

cal marker of adrenocortical carcinomas was reported byBertagna and Orth (16). They found that a daily 17-KS excre-tion of greater than 20 mg was strongly suggestive of carci-noma.In addition, Aupetit et al (17) recently reported thathypoaldosteronism with normal or somewhat elevated levels of

some aldosterone precursors may occur in adrenal carcinomas,but never in benign tumors. The latter biochemical criteria werenot applicable to the present patient, since she exhibited nohypoaldosteronism. Although the large tumor size (>6 cm) and

the extraordinarily high level of urinary 17-KS in this patientmight be suggestive of malignancy, the clinical history of thepatient revealed that her virilization started at 12 years of age,

approximately 10 years before admission, suggesting slowtumor growth and hence its possible benign nature. In fact, thesurgical and histological findings showed no evidence of malig-nancy, with neither microscopically visible extension beyondthe adrenal capsule nor apparent dissemination into the sur-rounding tissue. The uneventful clinical course after surgeryalso seems to support the tumor's benign character. In general,

however, the diagnosis of endocrinological tumors as de-

finitely benign is occasionally difficult, even when tissue isavailable for pathological examination. There is a recent casereport of an unusual adrenocortical carcinoma that recurred 1 6years after an apparently curative surgical excision (1 8). Thisdemonstrates the importance of a life-long follow-up of thepresent patient as well.

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5) Shimazaki J, Ichikawa T, Shiseki Y, Kuramochi H. Statistical review ofadrenal cortical carcinoma. Nippon Rinsho 51 (Suppl.): 766, 1993 (inJapanese).

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6) Bertagna C, Orth DN. Clinical and laboratory findings and results oftherapy in 58 patients with adrenocortical tumors admitted to a singlecenter(1951 to 1978). AmJMed71: 855, 1981.

17) Aupetit FB, Battaglia C, Zenatti M, Emeric BN, Legrand JC.Hypoaldosteronism accompanied by normal or elevatedmineralocorticosteroid pathway steroid: a marker of adrenal carcinoma.J Clin Endocrinol Metab 76: 38, 1993.

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