UNEVENTFUL DELIVERY FOLLOWING SERIES OF SUCCESSIVE TREATMENTS FOR VIRILIZED CUSHING SYNDROME DUE TO ADRENOCORTICAL CARCINOMA
TERUHIRO NAKADA, M.D. HIROSHI KOIKE, M.D. TAKASHI KATAYAMA, M.D.
From the Department of Urology, Faculty of Medicine, Toyama Medical and Pharmaceutical University, Toyama, Japan
ABSTRACT-A twenty-one-year-old virilized woman with Cushing syndrome due to a huge adrenocortical carcinoma was successively treated with trilostane (38-hydroxysteroid dehydro- genase inhibitor), subsequent adrenalectomy, and postoperative cis-platinum. Clinical or bio- chemical abnormalities peculiar to Cushing syndrome gradually subsided, and three and one-half years after the adrenal surgery, the patient delivered a normal female infant. This study points out some of the clinical and biochemical responses of each treatment.
Cushing syndrome in combination with preg- nancy has been recorded infrequently.1 Detri- ment of fertility appears to be caused by corti- costeroid suppression of gonadotropin-releasing hormone.2 A review of the literature revealed 38 pregnancies in 33 patients.1,3-6 The hypercor- tisolemia present in approximately one half of the pregnant patients was attributed to an adrenal cortical adenoma or carcinoma, while in the other half, the cause was adrenal cortical hyperplasia.3
We present a case of Cushing syndrome due to adrenocortical carcinoma which was succes- sively treated with trilostane, subsequent adrenalectomy, and postoperative cis-platinum (CDDP) to prevent tumor-spread, and in whom pregnancy and uneventful delivery fol- lowed three and one-half years after the adrenal surgery.
Case Report
A twenty-one-year-old woman was admitted complaining of a seven-month history of amenorrhea and hypertension in May, 1982. She also gave a history of hirsutism from the age of twenty. Menarche had occurred at the age of fifteen, and her periods had previously been
regular and normal. On physical examination, she appeared moderately obese and plethoric with a moon face. Supraclavicular fat deposits, thin extremities, purplish striae on the axilla, clitoromegaly, and terminal hair over the chin were observed. Blood pressure ranged from 162/108 mm Hg to 170/118 mm Hg. The hem- atocrit value was 38.5 percent and the hemo- globin value was 12.7 g/dL. The serum sodium level was 140, potassium 2.2, and chloride 98 mEq/L. Results of blood cell tests and differen- tial counts of white blood cells were within nor- mal limits. Blood chemistry disclosed total pro- tein 5.2-5.6 g/dL, serum alkaline phosphatase 3.2-3.4 KAU, serum lactic dehydrogenase (LDH) 410 IU, and serum total cholesterol 272- 290 mg/dL. The oral glucose tolerance test demonstrated a fasting blood glucose level of 172 mg/dL, and levels of 233 mg/dL at 1 hour, 268 mg/dL at 2 hrs, and 249 mg/dL at 3 hrs. The urine was straw-colored, with an alkaline reaction, a trace of albumin, and with 10-12 white blood cells and 2-3 red blood cells per high-powered field. Under a regular sodium diet, plasma aldosterone concentration was 5.9 pg/mL. Plasma renin activity was 0.9 ng/ml/ hr. Plasma angiotensins I and II were 22 pg/mL and 50 pg/mL. LH-RH test was negative.
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Plasma ACTH was low (20 pg/mL). Plasma cortisol levels were elevated (38-44 µg/dL). Urinary 17-hydroxycorticosteroid (17-OHCS) and ketosteroid (17-KS) excretions were ele- vated (22.5-32 mg/day and 112-138 mg/day, respectively). Each fractional steroid of urinary 17-KS was remarkably elevated as follows: an- drosterone 5.4, 7.4 mg/day; etiocholanolone
15.0, 16.0 mg/day; DHEA 21.7, 59.4 mg/day; 11-OH-androsterone 3.8, 4.3 mg/day; 11-OH- etiocholanolone 0.9, 1.8 mg/day; 11-ketoetio- cholanolone 1.4, 2.1 mg/day. Administration of 2 mg/day or 8 mg/day of dexamethasone for two days each failed to suppress the levels of urinary 17-OHCS or 17-KS excretion, respec- tively. These values were not significantly changed following ACTH administration.
An abdominal aortogram demonstrated that the right kidney was displaced by an ipsilateral large suprarenal mass. A computerized tomog- raphy (CT) scan demonstrated an inhomoge- neous oval mass in the right suprarenal area (Fig. 1). Scintillation scanning of the right adrenal gland using 75Se-scintardren demon- strated a normal left adrenal gland, but showed almost negligible uptake of radionuclide on the right side. These findings suggested Cushing syndrome due to right adrenocortical car- cinoma.
The patient was prescribed trilostane in in- creasing doses from 240 to 360 mg/day for twelve consecutive days (Fig. 2). This treat- ment was followed by a gradual rise in the urinary excretion of 17-KS and serum potas- sium. Levels of plasma cortisol showed a
TRILOSTANE
CDDP ( 50 mg × 5 )
360
240 ( mg/day )
Plasma
100
50
ACTH (pg/ml )
50
25
Plasma CORTISOL (ug/dl )
0
0
200
50
Plasma TESTOSTERONE
100
Plasma ESTRADIOL (pg/ml )
(ng/ml)
A
25
0
0
40
Urinary 17-OHCS (mg/day)
150
20
100
Urinary 17-KS (mg/day)
10
0
0
180
BP
4
(mmHg)
150
3
Serum K (mEq/L)
80
2
0
20
40
60
80
HOSPITAL DAYS
A
B
4
slightly decreased tendency. There was minimal to no definite change in plasma testosterone or plasma estradiol. Through an anterior trans- peritoneal approach, the right adrenal was re- sected.
The removed specimen was an irregularly encapsulated tumor, elastic-soft in consistency, measuring 11 × 10 x 9 cm and weighing 524 g. There was no manifestable evidence of tumor invasion of adjacent organs or tissues. The cut surface of the tumor was brown but some areas showed dark brown faci with hemorrhage or necrosis (Fig. 3A). Microscopically the tumor consisted predominantly of compact-type cells with eosinophilic granular, lipid-poor cyto- plasm. Some cancer nests possessed lipid-laden cells. Neoplasmic cells were separated by fine
fibrous stromas. The nuclei were pleomorphic and showed remarkable vesicularity. Some tu- mor cells had invaded the vascular wall. These findings conformed to a diagnosis of adrenal cortical carcinoma (Fig. 3B).
The adrenal surgery gradually improved the high blood pressure and hypokalemia (Fig. 2). Levels of plasma cortisol, plasma testosterone, and urinary excretion of 17-OHCS and 17-KS were normalized immediately after the surgery (Fig. 2), although the procedure caused a slight rising tendency of plasma ACTH. Plasma estra- diol remained unchanged following the surgery (Fig. 2). Three weeks after the operation, CDDP therapy was started with forced diure- sis. The patient showed good toleration of ad- ministration of 50 mg/day of CDDP every seven
| Date of Physical Examination | Plasma ACTH (pg/mL) | Plasma Cortisol (ug/dL) | Plasma Testosterone (ng/mL) | Plasma Estradiol (pg/mL) | Plasma LH (mIU/mL) | Plasma FSH (mIU/mL) | Urinary 17-OHCS (mg/day) | Urinary 17-KS (mg/day) |
|---|---|---|---|---|---|---|---|---|
| 5 months before conception | 57 | 11.9 | 0.4 | . . | . . | . . | 3.9 | 5.4 |
| 4 months before conception | 29 | 11.5 | 0.8 | .. | 2.5 | 5.4 | ||
| 2 months' gestation | 52 | 13.3 | 0.4 | 148 | 28 | 6 | 4.8 | 3.5 |
| 3 months' gestation | 41 | 12.9 | 0.7 | 172 | . . | . . | 5.0 | 7.0 |
| 4 months' gestation | 90 | 22.4 | 0.6 | . . | . . | .. | ||
| 5 months' gestation | 34 | 12.5 | 0.8 | 185 | . . | 4.1 | 5.4 | |
| 6 months' gestation | 37 | 16.8 | 1.2 | 896 | . . | 6.2 | 4.4 | |
| 7 months' gestation | 38 | 23.7 | 1.3 | 201 | 13 | 7.1 | 6.0 | |
| 8 months' gestation | . . | 31.6 | 1.6 | . . | 389 | 20 | . . | |
| 9 months' gestation | 46 | . . | 1.8 | 8700 | . . | . . | . . | |
| Vaginal delivery | ||||||||
| 2 weeks postpartum | 49 | 19.1 | 1.0 | . . | 43 | 12 | 4.6 | 5.0 |
| 3 weeks postpartum | 46 | 10.1 | 0.5 | 154 | 30 | 10 | 3.6 | 4.8 |
days for five sessions. The levels of examined hormones were not much affected by this drug therapy (Fig. 2). Features of her physical condi- tion, such as moon face, buffalo-hump obesity, amenorrhea, and purple striae, characteristic of Cushing syndrome, were gradually improved. During a follow-up period of three and one-half years, she remained normotensive (110-126/ 60-74 mm Hg) and asymptomatic.
She became pregnant in February, 1985. A persistent rise in plasma estradiol or plasma LH was associated with advancement of pregnancy (Table I). Levels of plasma ACTH, plasma FSH, and urinary excretion of 17-KS showed slight fluctuation, and it was difficult to find a specific tendency. She was admitted to the De- partment of Gynecology and Obstetrics, Toy- ama Medical and Pharmaceutical University, in November, 1985. Two days after admission, she went into spontaneous labor and a normal fe- male 3,426-g infant was delivered. Although plasma cortisol and urinary excretion of 17- OHCS caused slight elevations two months be- fore delivery, they returned to normal levels two weeks postpartum. One month postpar- tum, plasma cortisol revealed a normal circa- dian rhythm. Following delivery, there were no clinical signs of pituitary or adrenal insuffi- ciency in the patient and her infant. They were discharged and returned home for further con- valescence, and have since been asymptomatic (Fig. 4).
Comment
Among the reported pregnancies occurring during active Cushing syndrome, at least 30 percent have ended in spontaneous abortion or stillbirth, while 25 percent have resulted in pre- mature delivery.4,7 A great amount of cortisol secretion is known to suppress the maternal and fetal secretion of adrenal dehydroepiandro- sterone (DHEA) or 16x-hydroxydehydroepian- drosterone (16a-OH DHEA), resulting in de- creased estradiol production.3,8 We did not de- termine these steroids in this patient, but increased levels of plasma DHEA and DHEA- sulfate associated with decreased levels of 84-an- drostenedione, probably resulting in decreased estradiol secretion, have been confirmed in sub- jects treated with trilostane.9 Indeed, a low level of urinary estradiol in a patient with Cushing syndrome due to adrenal adenoma has been reported.3 In our patient, urinary estra- diol increased during gestation, and returned to a normal level after delivery. This suggests that
A
B
glucocorticoids were working physiologically during the period of pregnancy. Although a pa- tient with Cushing syndrome due to adrenal cortical adenoma in whom hypercortisolemia disappeared during the third trimester of preg- nancy has been described in a previous report,5 pregnancy should probably be avoided in this type of patient until complete cure of the syn- drome.
Adrenalectomy alone for massive adrenal carcinoma invariably carries a high risk of re- currence or distant metastasis to the lung, liver, or lymph nodes.10 Indeed, according to the clinical staging proposed by Sullivan and associ- ates,11 our case was a Stage II adrenal tumor as heavy as 524 g. Survival appears to be closely related to stage. The five-year survival rate for Stage II adrenal tumor should be no greater than 80 percent, and this decreases to only 50 percent in ten years. In patients with Stage III disease, 11 percent are alive after five years and none after ten years. Of patients with Stage IV adrenal tumor, 8 percent are alive at one year and none are alive after ten years.10 As for the cure rate after surgery, radiation alone or a combination of routine chemotherapy is never effective. Mitotane [1,1-dichloro-2-(0- chlorophenyl)-2 (p-chlorophenyl)-ethan, op’- DDD] has been demonstrated to reduce the se- cretion of adrenocortical hormones concomitant with occasional occurrence of de- generative changes of the adrenal cortex.12 In
addition, some subjects have been shown to re- spond objectively to this chemotherapeutic agent, although the mean duration of response is only ten months.13 In view of the poor prog- nosis of patients with advanced adrenal car- cinoma, low-dose but long-term op’-DDD therapy has been advocated as adjuvant therapy even in the absence of clinically evident metastases. 14 On the other hand, CDDP may be one of the most active agents for germ cell tu- mors, bladder cancer, or ovarian tumors.15 Re- cently CDDP therapy was given to 4 patients with metastatic adrenocortical carcinoma and an objective response in each patient was achieved.16 The drug has also been adminis- tered by previous investigators in a variety of doses with or without other chemotherapeutic agents.16 Our CDDP therapy might be criti- cized for its small dosage, but to obtain com- plete cure of the disease and to assess the value of CDDP, a trial was performed using this drug alone. Further experience is required in this re- gard. Major adrenal androgen of tumor origin could be clearly estimated by monitoring the levels of plasma testosterone in this patient (Fig. 2), and this hormone could therefore be re- garded as a useful tumor marker. The level of plasma testosterone continued to remain within the normal range following CDDP treatment (Fig. 2).
Excessive secretion of adrenal cortisol in pa- tients with Cushing syndrome frequently ac- companies hypokalemia, friable tissue, and postoperative complication, such as infection or deficient wound healing. In our patient, pre- operative trilostane therapy improved the hy- pokalemia (Fig. 2). We stopped the medication after a relatively short period because we highly suspected adrenocortical carcinoma. However, in patients with pituitary-dependent Cushing disease or Cushing syndrome due to adrenocor- tical adenoma, more prolonged treatment with trilostane appears to improve the clinical and biochemical parameters by lowering the corti-
sol secretion rate. Further details of therapeutic experiences with this drug can be obtained from other reports. 9,17
Department of Urology School of Medicine Chiba University 1-8-1, Inohana, Chiba 280 Japan (DR. NAKADA)
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