Virilizing Adrenocortical Tumors in Adult Women
Report of 10 Patients, 2 of Whom Each Had a Tumor Secreting Only Testosterone
Antonio Del Gaudio, M.D. F.I.C.S., and Giovanni-Alberto Del Gaudio, M.D.
Background. Virilizing adrenocortical tumors are uncommon in adult women. These lesions generally se- crete dehydroepiandrosterone (DHEA) and dehydro- epiandrosterone sulfate (DHEAS), but not testosterone, which usually is produced by ovarian tumors. Excep- tionally, adrenal growths may give off testosterone and no other assessable androgen. The detection of the site of excess testosterone yield is paramount for proper sur- gery. The true nature of the growth often is unpredict- able, even at the time the pathologist examines the surgi- cal specimen.
Methods. The workup in a virilized adult woman re- lies on biochemical tests such as 24-hour urinary 17-KS and 17-OHCS levels and plasma corticosteroid levels (tes- tosterone, DHEA, DHEAS, and androstenedione), and on modern imaging studies such as ultrasonography, com- puted tomography, and digital angiography.
Results. Among a series of 190 adrenal tumors col- lected in the last 30-year period, only 10 virilizing growths (5.3%) were detected. Two cases of virilization mixed with cushingoid features were observed. In two other cases, reported in detail, the tumor secreted testos- terone only, without other assessable androgens. Seven of the 10 tumors were malignant.
Conclusions. In cases of tumors secreting testoster- one only, high-resolution imaging has contributed signifi- cantly in pinpointing the site of the growth, whereas dy- namic hormone testing, using selective stimulation or suppression studies, has been misleading. The malignant nature of the growth may be revealed only by the pres- ence of metastases, because pleomorphism and capsular and vascular invasion have been detected histologically in clinically benign tumors. The prognosis for large tu- mors usually is dismal. Cancer 1993; 72:1997-2003.
Key words: adrenocortical tumors, virilization, testoster- one, androgens, hypercorticism.
Virilizing adrenocortical tumors are uncommon in adult women. Among a series of 190 adrenal tumors collected in our unit over the last 30 years, only 10 virilizing growths (5.3%) were detected. In two of these cases, the rare association of virilization and cushingoid clinical features was found. Androgen-secreting adrenocortical tumors, however, are more common in childhood.1-3
These growths usually secrete dehydroepiandros- terone (DHEA) and dehydroepiandrosterone sulfate (DHEAS), but not testosterone, which generally is pro- duced by ovarian tumors. Exceptionally, adrenal tu- mors may secrete testosterone only, and no other assess- able androgen, because the urinary 17-KS levels usually are within normal values. Up to 1987, Mattox and Phelan4 collected 47 cases, including their single case report, of virilizing adrenal cortex tumors secreting only testosterone. Two further observations are in- cluded in our series. The prerequisite for proper therapy of these virilized women is the detection of the site of the excess testosterone production. The advent of high- resolution imaging has contributed significantly in pin- pointing the tumor, whereas dynamic hormone testing, using selective stimulation or suppression studies, has been misleading.5
In the absence of metastases, the malignancy of the growth is unpredictable; however, most cases should be considered so6; 7 of the 10 tumors in our series were malignant.
Patients and Methods
Our series of virilized adult women with adrenal tu- mors comprises 10 cases (average age, 44.6 years; range, 20-66 years) (Table 1).
The clinical findings were some or all of the follow- ing: hirsutism (Fig. 1), male-pattern baldness, deep
From the Department of Surgery, University of Bologna, Italy. Address for reprints: Antonio Del Gaudio, M.D., Istituto di Pa- tologia Speciale Chirurgica, Ospedale S. Orsola, Bologna, Italy 40138. Accepted for publication April 22, 1993.
| Patient no. | Year of observation | Age (yr) | Delay from 1ª symptom to diagnosis (mo) | 17-KS | Hormonal pattern | Diagnostic tests | Site | Nature | Notes | Outcome | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| DHEAS | Andro- stenedione | Testo- sterone | ||||||||||
| 1 | 1960 | 61 | 30 | ++++ | Urography | Right | Malignant | Inoperable | Died (within 3 mo) | |||
| 2 | 1964 | 59 | 36 | ++++ | Urography | Left | Malignant | Explored liver metastasis | Died (within 3 mo) | |||
| 3 | 1968 | 43 | 32 | +++ | Urography | Left | Benign | Left adrenectomy | Alive and well | |||
| 4 | 1971 | 48 | 3 | ++++ | Urography Pnemoretrop Angiography | Right | Malignant | Explored liver metastasis | Died (within 1 mo) | |||
| 5 | 1972 | 33 | 19 | = | = | + | ++++ | Angiography | Left | Malignant | Left adrenectomy | Died (16 mo later) |
| 6 | 1980 | 20 | 12 | ++++ | +++ | + | + | Urography CT | Right | Malignant | + Cushing syndrome, right adrenectomy + nephrectomy | Died (6 mo later) |
| 7 | 1985 | 45 | 18 | ++ | ++ | ++ | + | ECHO CT | Right | Benign | + Cushing syndrome, right adrenectomy | Alive and well |
| 8 | 1989 | 66 | 18 | ++ | + | + | = | ECHO CT Scint .- Angio. | Right | Benign | Right adrenectomy (4 cm) | Alive and well |
| 9 | 1989 | 47 | 4 | +++ | +++ | ++ | ++ | ECHO CT Angiography | Right | Malignant | Right adrenectomy g 400 (12 × 10 cm) | Alive and well |
| 10 | 1990 | 24 | 12 | + | = | + | ++++ | ECHO CT | Lefi | Malignant | Left adrenectomy (cm 15) | Alive and well |
| Angiography | ||||||||||||
DHEAS: dehydroepiandrosterone sulfate; CT: computed tomography; pnemoretrop: pneumoretroperitoneoroentgenography; ECHO: echotomography.
a
b
C
voice, acne, male musculature, irregular menses or amenorrhea, clitoromegaly, increased libido, and palpa- ble abdominal mass. Two patients had an associated clinical and hormonal Cushing syndrome (Cases 6 and 7; Fig. 2), whereas the adrenal tumor in two others (Cases 5 and 10) secreted only testosterone, and these are reported in detail. The overall mean time interval between first symptom and diagnosis was 18.4 months.
The usual workup consisted of routine biochemical assessment of the 24-hour urinary 17-KS and 17- OHCS levels, and plasma corticosteroid levels (testos- terone, DHEA, DHEAS, and androstenedione). In some cases, dynamic hormone tests had been performed, and modern imaging studies also have become very helpful. To verify whether these tumors were benign or malig- nant, we had to rely not only on the pathologist’s re- port, but also on the presence of metastases, and the evolution of the clinical features and biochemical indi- ces after treatment (Fig. 3).
a
b
Case Reports
Case 5
A 33-year-old woman sought medical advice after a 19- month history of secondary amenorrhea, deepening of the
a
b
a
b
C
d
S
.
a
b
c
voice, acne, and a hirsutism so severe as to require a shave twice a week (Fig. 4A, B). She was normotensive and had no cushingoid features. Her gynecologist had prescribed hor- mone therapy to normalize her periods. Menarche had oc- curred at the age of 11 years, and 13 years later she had a successful pregnancy. At physical examination, a large, round mass was found in the left hypochondrium. Pelvic examina- tion was entirely negative except for clitoromegaly.
The laboratory findings were as follows: normal serum electrolytes; urinary 17-KS was 7.4 mg/24 hours (normal range, 9 ± 2 mg/24 hours); the poststimulation and suppres- sion serum testosterone levels, in the 13 samples taken on each of the 10 consecutive days, were constantly between 317 and 406 ng/100 ml, with a mean of 357 (normal range, 64 ± 14 ng/100 ml); the morning cortisol level was 12.6 y/100 ml (normal range, 5-25 y/100 ml); and the serum 178-estradiol was 87.7 pg/ml (normal range, 37-407 pg/ml, in follicular phase). A selective left adrenal angiogram showed a typical arcuate arrangement of the arterial branches with an early injection of the veins and some irregular contrast-filled pools, persisting late in the venous phase (Fig. 4D).
Left adrenalectomy through a median laparotomy re- vealed a 12-cm adrenal mass provided with a well vascular- ized capsule (Fig. 5A, B). The pathologist identified the mass as an adrenocortical carcinoma with aspects of vascular infil- tration (Fig. 5C). Removal of the adrenal tumor resulted in complete patient recovery. Controls 1 month after surgery showed serum testosterone level at 43 ng/100 ml; urinary 17-KS 6.1 mg/24 hours; total estrogens at 85 y/24 hours (normal, 30-60 y/24 hours). Four months after surgery, the patient’s menstruations returned to normal and the acne and beard disappeared (Fig. 4℃).
Twelve months after surgery, acne reappeared, followed by hirsutism and dysmenorrhea with an episode of severe hyperglycemia. Urinary 17-KS and 11-HOCS levels were normal, but serum testosterone again was elevated (930 ng/
100 ml). The abdomen was distended by ascites and hard lumps were palpated in the left flank. Four months later she died of diffuse recurrent disease.
Case 10
A 24-year-old woman was admitted for hirsutism and left adrenal tumor. She had had menarche at the age of 14 years, and 5 years later she had a successful delivery followed by regular menses until the age of 23 years. At the age of 21 years, she started to note the growth of coarse hair all over the posterior portions of her legs, gradually affecting the entire
a
b
body (Fig. 6A). By the age of 23 years, she shaved her face and legs daily and occasionally the abdomen and chest. She had also noticed a deepening of her voice and some increase in her libido.
The physical findings were typical of a masculinized woman, with severe hirsutism, temporal alopecia, and an un- usually enlarged clitoris. During an earlier admission to the endocrinology unit, she was found to have an elevated serum testosterone level (670 ng/100 ml) with a normal 17-KS level, and the DHEA was 2.6 ng/ml (normal range, 4-27 ng/ml). In an attempt to suppress the hirsutism, 5 mg of prednisone were administered twice a day orally for 2 weeks; however, hair continued to grow. Ultrasonography detected a large, 9.5 × 5.5 cm mass with a relatively homogeneous echostructure and a thin hyperechogenic periphery, in the left adrenal gland area; computed tomography (CT) scan confirmed the presence of a large mass with significant enhancement, diag- nostic of an adrenal tumor (Fig. 6B); digital angiography re- vealed only indirect signs of a poorly vascularized growth in front of the upper pole of the left kidney.
At surgery, a well capsulated, 15 × 7 × 5 cm, twin-no- duled tumor of the left adrenal gland, weighing 170 g, was removed (Fig. 7A, B). The pathologist diagnosed a sarcoma- like, highly anaplastic adrenal carcinoma with some areas of hemorrhage and necrosis (Fig. 7C-E). Within 4 months after surgery, the acne regressed and the hirsutism improved. The serum testosterone level returned to normal values (100 ng/ 100 ml). The patient is alive and well 22 months after surgery, with no signs of recurrence.
Discussion
Adult female virilization may be caused by tumors usually located in the ovary, and rarely in the adrenal gland.
There are three naturally occurring androgens re- sponsible for androgenic end-organ stimulation: DHEA, androstenedione, and testosterone. A small part of the testosterone, and all of the other hormones, are metabolized to androsterone and etiocholanolone, as- sessable as urinary 17-KS. DHEA and DHEAS seem to be secreted in higher amounts by adrenal tumors, and this probably accounts for the high 17-KS urine levels in patients with these growths. In adrenocortical tu- mors secreting DHEA and androstenedione, the serum testosterone level may be elevated because of periph- eral conversion.
Because virilizing ovarian tumors produce less DHEA and DHEAS than virilizing adrenal tumors, the urinary 17-KS level may be normal or even low. These tumors are believed to produce mainly testosterone, with levels of DHEA below normal values.
The finding of high testosterone levels in a virilized female patient is regarded as evidence of an ovarian tumor; however, testosterone-secreting adrenal neo- plasms with normal 17-KS levels have been reported. Furthermore, the selective venous sampling in Kogan et
O
a
d
b
e
al.’s case7 clearly demonstrated that the testosterone originated from the adrenal gland, and not as the result of peripheral conversion. Givens et al.8 maintain that virilizing adrenal tumors cause a rise in serum testoster- one values, with low or normal urinary 17-KS levels, because the enzyme system may be so active as to con- vert the androstenedione (the prevailing adrenal an- drogen) into testosterone. In fact, in Kelly et al.’s obser- vation,9 the 50-fold increase in 17-8-hydroxysteroid- dehydrogenase activity caused an isolated testosterone overproduction, by the conversion of androstenedione directly into testosterone. Aguirre and Scully10 sug- gested that the adrenal tumors secreting only testoster- one may have originated from gonadal cells displaced within the adrenal gland. Vasilof et al.11 supported this theory by finding inclusions specific for gonadal Leydig cells in three cases of virilizing adrenal tumors.
This theory also explains the paradoxical response to stimulation and suppression tests, which may be re- lated to the mutual embryonic origin of the two glands.12 In the past, dynamic endocrine testing had been proposed to identify whether the source of the androgens was the ovary or the adrenal gland; how- ever, it later was found that the adrenal gland some- times was stimulated by human chorionic gonadotro- pin, and that ovarian tumors reacted to adrenocortico- tropic hormone,8,13,14 and therefore the stimulation and suppression tests were unreliable in pinpointing the site of excess androgenic production. The presence of ec- topic functional human chorionic gonadotropin recep- tors in adrenal tumors also has been suggested to eluci- date this paradoxic response.15
Adrenal venography and retrograde sampling in the adrenal and ovarian veins to assess for a gradient in testosterone levels may locate the source of excess an- drogens, but results may be misleading, because on the left side both the adrenal and ovarian veins drain into the renal vein. Selective adrenal angiography is ideal when dealing with large tumors (Fig. 8), and from a functional point of view, the iodocholesterol adrenal scan, with dexamethasone suppression, shows a consid- erable uptake on the side of the growth, revealing a functioning adrenocortical tumor.
For adrenocortical tumors secreting testosterone only, the diagnosis can be made based on features of virilization, elevated serum testosterone levels, the de- tection of an adrenal mass, and absence of ovarian growths. It is important to be aware of this kind of adre- nal virilization, because too many oophorectomies al- ready have been performed8,9,12,13,16 for a suspected vir- ilizing ovarian tumor before the true “culprit” behind the high testosterone level was unmasked at the adre- nal gland level. One patient had been submitted to two laparoscopies plus a venous catheterization before the adrenal adenoma was found.17
a
b
0
d
5€
51
52
5
54
55
rf
Assessing whether the growth is benign or malig- nant is rather difficult, even when the surgical speci- men is examined histologically, because pleomorphism and capsular and vascular invasion have been detected in clinically benign tumors. Malignancy may be re- vealed only by the presence of metastases. Patients with very high 17-KS levels and clinical manifestations of virilization probably have an adrenal carcinoma.9 Prognosis usually is dismal for large tumors. In the last two cases of our series, however, in spite of large tu- mors, the patients are still alive, but the follow-up is limited.
Conclusions
Adult female virilization may be caused by tumors lo- cated in the ovary or in the adrenal gland. The detection of the site of the tumor is a prerequisite for proper ther- apy. Hormonal test results are not reliable for this pur- pose, nor are dynamic endocrine tests. Modern imaging
studies such as ultrasonography, CT, and digital angiog- raphy permit the growth to be pinpointed. The removal of the tumor when it still is small carries a favorable prognosis, but this requires a high degree of clinical suspicion.
References
1. Lee PDK, Winter RJ, Green OC. Virilizing adrenocortical tumors in childhood: eight cases and a review of the literature. Pediatrics 1985; 76:437-44.
2. Cacciari E, Cicognani A, Pirazzoli P, Paolucci G, Mancini A, Tassinari D, et al. Adrenocortical tumours in children: our experi- ence with nine cases. Acta Endocrinol 1986; 279:264-74.
3. Salt AT, Savage MO, Grant DB. Growth patterns after surgery for virilizing adrenocortical adenoma. Arch Dis Child 1992; 67:234-6.
4. Mattox JH, Phelan S. The evaluation of adult females with tes- tosterone producing neoplasms of the adrenal cortex. Surg Gyne- col Obstet 1987; 164:98-101.
5. De Lange WE, Pratt JJ, Doorenbos H. A gonadotrophin-respon- sive testosterone producing adrenocortical adenoma and high gonadotrophin levels in an elderly woman. Clin Endocrinol 1980; 12:21-8.
6. Chevrel JP, Lafleur A, Attali JR, Modigliani E. Virilizing tumors of the adrenal glands: a propos of 3 cases. J Urol 1989; 95:309- 11.
7. Kogan BA, Sonda PL, Diokno AC. Virilizing adrenal adenoma secreting testosterone. J Urol 1981; 126:787-8.
8. Givens JR, Andersen RN, Wiser WL, Coleman SA, Fish SA. A gonadotropin-responsive adreno-cortical adenoma. J Clin Endo- crinol Metab 1974; 38:126-33.
9. Kelly TR, Mayors DJ, Boutsicaris PS. Adrenal adenoma: isolated testosterone secretion. Am Surg 1982; 48:604-6.
10. Aguirre P, Scully RE. Testosterone-secreting adrenal ganglioneu- roma containing Leydig cells. Am J Surg Pathol 1983; 7:699-705.
11. Vasiloff J, Chideckel EW, Boyd CB, Foshag LJ. Testosterone-se- creting adrenal adenoma containing crystalloids characteristic of Leydig cells. Am J Med 1985; 79:772-6.
12. Trost BN, Koenig MP, Zimmermann A, Zachmann M, Müller J. Virilization of a post-menopausal woman by a testosterone-se- creting Leydig cell type adrenal adenoma. Acta Endocrinol 1981; 98:274-82.
13. Werk EE, Sholiton LJ, Kalejs L. Testosterone-secreting adrenal adenoma under gonadotropin control. N Engl J Med 1973; 289:767-70.
14. Takahashi H, Yoshizaki K, Kato H, Masuda T. A gonadotro- phin-responsive virilizing adrenal tumor identified as a mixed ganglioneuroma and adrenocortical adenoma. Acta Endocrinol 1978; 89:701-9.
5. Leinonen P, Ranta T, Siegberg R, Pelkonen R, Heikkila P, Kahri A. Testosterone-secreting virilizing adrenal adenoma with hu- man chorionic gonadotrophin receptors and 21-hydroxylase de- ficiency. Clin Endocrinol 1991; 34:31-5.
16. Dolinar R, Burch WM. Testosterone-producing adrenal ade- noma in a woman with normal urinary 17-Ketosteroid levels. JAMA 1983; 250:2504-5.
17. Spaulding SW, Masuda T, Osawa Y. Increased 17 8-hydroxy- steroid dehydrogenase activity in a masculinizing adrenal ade- noma in a patient with isolated testosterone overproduction. J Clin Endocrinol Metabol 1980; 50:537-40.