Recurrence of Adrenal Carcinoma During Pregnancy with Delivery of a Normal Child
H. BANK, R. BEER, B. LUNENFELD, E. RABAU, AND G. RUMNEY1
Department of Endocrinology, Tel-Hashomer Government Hospital, Israel
ABSTRACT. A case of adrenocortical car- cinoma, in a 24-yr-old woman who has to date survived 8 years, is presented. A number of findings have been discussed, such as the local recurrence of the tumor during a third preg- nancy, the demonstration of a partial pla-
cental barrier to cortisol, the birth of a normal child with well-functioning adrenals in the presence of high levels of maternal cortisol, and the management of pregnancy in the presence of functioning adrenocortical car- cinoma. (J Clin Endocr 25: 359, 1965)
I N THE LITERATURE, pregnancy in women with adrenal carcinoma is a rare occurrence. In over 300 patients reviewed, only four instances of preg- nancy have been reported. In two of these (1), the existence of the tumor at the time of pregnancy could only be in- ferred from the history of the patient, the tumor, in fact, being found only one year later. In the third patient (2), a subsequent pregnancy occurred after re- moval of a malignant tumor and the patient was delivered of a second normal child in the presence of a functioning metastatic growth of the liver. In neither of these patients were biochemical studies done during pregnancy, labor or in the post-partum period. The fourth patient (3) had two pregnancies-one ending in abortion, the other in a normal term infant during the course of an adreno- cortical carcinoma.
In this study we wish to present a case of adrenocortical carcinoma in a 24- year-old woman who has, to date, sur- vived eight years.
Received June 26, 1964; accepted October 23, 1964.
1 Dept. of Steroid Biochemistry, Beilinson Hospital.
Materials and Methods
Urinary 17-ketosteroids (17-KS) were determined by the method of Hamburger and Rush (6), the 17-hydroxycorticosteroids (17-OHCS) and ketogenic steroids by the method of Appleby and Norymberski (7). Urinary dehydroepiandrosterone (DHE), androsterone and etiocholanolone were de- termined after solvolysis (8) by the chro- matographic procedure of Rubin et al. (9). Plasma cortisol was determined by the method of Peterson et al. (10).
For the extraction of urinary gonado- tropins, the method of Klinefelter et al. (11) was used (without dialysis) and the uterine weight of intact immature mice served as the bio-assay end-point. The results are ex- pressed in mg equivalents of the Interna- tional Reference Preparation for Human Menopausal Gonadotropin (IRP-HMG).
Case Report
The patient, a 24-yr-old woman, when first seen in October, 1955, was referred to the Endocrine Outpatient Department for excessive weight gain. Her general appear- ance suggested Cushing’s syndrome and she was admitted for investigation.
There was nothing of note in the previous history. Menstrual periods commenced at the age of 14 and were regular with a 29- to 31-day cycle and usually lasted 4-5 days. She was married 4 years prior to hospitaliza- tion. In the 3 years following her marriage, she voluntarily abstained from pregnancy, but in the fourth year she was unable to
| 8:00 AM | 12 | 4 PM | 8 | 12 | 4 AM | 8 |
|---|---|---|---|---|---|---|
| 41.6 | 44.1 | 45.0 | 44.1 | 43.3 | 49.6 | 49.2 |
become pregnant. Symptoms appeared 7 months prior to admission, when she began complaining of general weakness, persistent headache and backache and cessation of menstruation.
She gained weight steadily, noticed round- ness and redness of the face, and was bothered with acne on the face and anterior chest. The increase in body fat she noticed particularly around the neck, hips and abdomen, while the limbs remained thin. She added some 7 kg to her weight in 7 months. Three months previously an at- tempt to produce a menstrual period by hormone treatment was unsuccessful, and soon after this she noticed the appearance of hair in the beard area on the chest and breasts. She had a brief return of menstrual flow 6 weeks prior to admission.
On examination, she had the typical Cushingoid facies with hirsutism (Fig. 1). Fat deposition at the back of the neck gave the appearance of “buffalo” hump, and on the rest of the body the fat was distributed as noted in the history. There were no striae to be seen on the abdomen and there was no definite bone tenderness. Acne was present on the face and on the chest between the breasts. The pulse was regular, the heart normal, and the lungs were clear. The blood pressure was 180/120 on this occasion (but subsequently varied considerably between 130-180 systolic and 80-120 diastolic). There were no abnormal neurological signs. Fundi were normal. Visual fields on perim- etry were normal.
Gynecological examination revealed no abnormalities. Laboratory findings further supported the clinical diagnosis. Hemoglobin was 16.4 g. A 5-hr glucose tolerance curve was diabetic. Urinary 17-ketosteroid (17-KS) values were in the region of 35.3 mg/day. Urinary gonadotropins ranged between 39 and 50 mg equivalent/HMG-IRP.
Skull roentgenograms were negative and there was no osteoporosis of vertebral bones. In the intravenous pyelogram, the left kidney was lower than normal. On presacral
insufflation, combined with tomography (Fig. 2), a tumor shadow the size of a small mandarin orange was outlined between the upper pole of the left kidney and the lower splenic border in the region of the left adrenal gland. On the right the films sug- gested a normal appearance of the adrenal gland.
The rapid development of the clinical picture suggested tumor rather than hyper- plasia. Twelve days after admission, the left suprarenal area was explored by the translumbar route, after a preparatory course of cortisone and ACTH. A tumor, weighing 320 g, was found replacing the suprarenal gland. It was irregular, hard and bluish-red in color. The tumor was encapsulated, not bound to the surrounding tissues and could be totally removed. The histological diag- nosis was adrenocarcinoma. This was based on the demonstration of a tumor of adrenal tissue with areas of irregular arrangement of tumor cells with pyknotic nuclei, extensive mitosis and degeneration. (The pathologist added the reservation that tumors of endo-
crine organs do not always conform to morphological criteria of malignancy and that there are pitfalls in the histological diagnosis.)
The postoperative course was uncompli- cated. The blood pressure remained normal at 120/80. The glucose tolerance curve was normal and vaginal smears postoperatively showed estrogenic activity. Within 6 weeks a typical ovulatory cycle could be demon- strated. The urinary 17-KS levels were nor- mal, ranging between 6.5 and 8 mg/day.
By January, 1956, the hirsutism had all but gone, she was feeling exceedingly well and had lost weight. Her periods were nor- mal for the next 2 months and in March, when there was a delay in menstruation for 2 weeks, she was found to be pregnant. Preg- nancy was normal throughout, and in De- cember, 1956, she was delivered of a normal girl weighing 2.750 kg.
One and a half yr later, in June, 1958, a second pregnancy was terminated at the third month.
During the ensuing 1} yr her condition re- mained good. Her only complaint was inter- mittent pain in the left loin. Urinary 17- ketosteroid levels done at intervals were normal, ranging between 4 and 12 mg/day.
In July, 1959, 4 years after her operation, she was again pregnant. There was a gradual usual weight gain in the first months of preg- nancy. Blood pressure was normal at 120/80. At the beginning of the third trimester, there was a sudden increase of weight from 72 to 78.5 kg, fullness of the face, rapid deposition of fat at the back of the neck and reappear- ance of hirsutism (Fig. 3). The glucose toler- ance test was diabetic, the urinary 17-KS be- tween 45 and 85 mg/day, and 17-ketogenic steroids 45-60 mg/day. 17-Hydroxycorti- costeroids (17-OHCS) were 46-53 mg/day. The plasma corticosteroids (Porter-Silber chromogens) were 45 ug/100 ml. The fetus was viable and it was decided to terminate pregnancy at the end of the eighth month.
At cesarean section, a male child, weigh- ing 2.850 kg, was delivered. At the opera- tion, manual exploration located a tumor, the size of an orange, at the site where the previous tumor had been removed. At the time of the cesarean section, retroplacental blood was sampled, as was cord blood. The Porter-Silber chromogens were 69.5 in the retroplacental blood and 17.0 µg/100 ml in the cord blood.
In the 12 days between the cesarean sec- tion and operation for removal of the tumor, a number of investigations were done, to be described below.
Pyelography and tomography of the left side revealed the large tumor mass. At oper- ation, by the transthoracic route, a tumor mass, weighing 350 g, was resected. Left nephrectomy was necessary for technical reasons. The tumor was encapsulated, but the capsule was broken in a number of places and there were further tumor-like masses extending as far as the aorta. As much of this as possible was removed. The histology was very similar to that of the previously re- moved tumor, with the exception that the capsule was broken and blood vessels were infiltrated with tumor cells.
The patient received cortisone immedi- ately after excision of the tumor. Postoper- atively, cortisone and ACTH were given intramuscularly and the dosages were gradu- ally reduced. Within 9 days, the blood pres- sure was stabilized at 130/90, and both could be discontinued.
There were no postoperative complica- tions and she was, in fact, very well. Ten days postoperatively a course of deep x-ray therapy, to the left suprarenal area, was commenced. Five weeks later she had a menstrual period and periods have been normal since. The signs of Cushing’s syn- drome receded gradually. Three months later, the hair on the face had disappeared (Fig. 4). 17-KS and 17-OHCS were repeated at 3-month intervals and have not deviated from the normal range for patients of her age and weight group. She became pregnant again 3 years after the operation. This preg- nancy was terminated on our advice. She has now been under observation for 4 years since the second operation.
The child. At birth, the electrolytes were nor- mal and blood glucose was 44 mg/100 ml. On the 21st day an ACTH test augmented his plasma Porter-Silber chromogens from 7.7 to 41.0 mg/100 ml (2 hr after a single in- jection of 5 IU of ACTH intravenously). Further development as to weight and size was normal during the 4-yr follow-up period.
Investigation in the mother after the cesarean section
(a) No diurnal variations (45.2+4.1 mg/ 100 ml) in the plasma Porter-Silber chromo- gens of the mother, 7 days after the cesarean section, were noted (Table 1).
(b) An ACTH test (25 IU in 500 ml saline iv for 4 hr) produced no marked change in
the plasma Porter-Silber chromogens (49.2- 50.2 ug/100 ml), or urinary 17-OHCS (58.9 and 57.0 mg). The urinary 17-KS increased somewhat from 52.8 to 90.7 mg.
(c) The dexamethasone (9x-fluoro-118- 17,21-trihydroxy-16x-methyl-41.4-pregnadiene- 3,20-dione) suppression test (8 mg/day in divided doses) provoked no significant changes in the steroid excretion pattern. Urinary 17-KS level was 58 mg before and 53 mg after the test and urinary 17-OHCS was 34 and 39 mg, respectively.
(d) The urinary dehydroepiandrosterone (36-hydroxy-45-androsten-17-one) was 4.5 mg/day (approximately 10% of the total 17-KS). From paper chromatography of 17- KS, the ratio of the total etiocholanolone to total androsterone was approximately 4.6:1 (normally the ratio is 1:1).
(e) The androsterone sulfate was 1.7 mg/24 hr (normal <0.4).
Discussion
The eight-year survival raised the question whether the histology of the tumor really represented malignancy. This point has been belabored in the literature (5, 12) and as yet no hard and fast criteria have been established. The diagnosis was based on the size of the tumors, the cell types with numerous pyknotic nuclei and mitoses, and the
invasion of blood vessels and capsule by tumor cells, in the recurrent growth, which at operation extended in masses as far as the aorta. These are criteria given by Symington et al. for distinguish- ing carcinoma from adenoma (13). The laboratory tests previously mentioned, especially the lack of ACTH responsive- ness with a relative lack of dexametha- sone suppression and the exceedingly high steroid values, have been accepted as further support for malignancy. Ex- ceptions have been reported (15). Some 5% of malignant tumors respond to ACTH and the lack of dexamethasone suppression has been shown to occur in some cases of adrenal hyperplasia, as in ACTH-secreting tumors of extra-abdom- inal origin, such as bronchogenic car- cinoma. The relatively low value of de- hydroepiandrosterone does not neces- sarily rule out malignancy. The long survival may have been a point against malignancy, but survival up to 11 years has been reported (4).
The third pregnancy occurred during a period when the growth was apparently quiescent and the patient conceived when definite evidence for active hyper- corticism was lacking. Pregnancies dur- ing evident Cushing’s syndrome have been reported rarely, but do occur (1-3).
In the present patient there was the rapid development during pregnancy of active hypercorticism, which presented many problems of management.
As the child was viable, a decision had to be made as to the time of termination of the pregnancy, to give both the mother and child the greatest possible chance for survival. It was therefore decided to terminate the pregnancy at the end of the eighth lunar month by cesarean sec- tion for the following reasons: to obviate any possibility of hemorrhage into tumor in late pregnancy and labor; to consider the obstetric management as for diabetic
mothers in general; not to delay surgery for possible adrenal tumor which was producing the rapid onset of the features of Cushing’s syndrome; to locate man- ually the site of the tumor, if present.
It was considered unwise to perform the removal of the tumor at the time of the cesarean section. The rare combina- tion of delivery in the presence of marked hypercorticism gave us the opportunity of confirming Migeon’s (19) view that the plasma Porter-Silber chromogens in the mother are three times higher than the plasma levels of the newborn. We were able to obtain retroplacental blood as well as umbilical blood and could demonstrate that even at extreme levels of cortisol there exists a partial barrier in the placenta in the ratio of 4:1. Interpretation of the ratio of cortisol in maternal and fetal plasma is made diffi- cult by the significant increase in cortisol- binding protein which occurs during the latter part of pregnancy in the maternal circulation. This is probably due to the much greater amount of transcortin in the maternal circulation than in that of the fetus. However, a partial placental barrier undoubtedly exists (18).
Reports (17) of malformation in chil- dren born to mothers who received high dosage of steroids during pregnancy for various conditions have appeared in the literature, and of course many other re- ports of normal babies have appeared as well. The question always arises in studies of humans whether the findings are purely coincidental. There is no doubt from the four-year follow-up study that a normal baby with well-function- ing adrenals from the onset can be born to a mother even with exceedingly high steroid levels. It should be noted, how- ever, that the high levels of steroids were found relatively late in pregnancy.
X-ray therapy to adrenal carcinoma is generally considered to be ineffective.
We speculate whether the four-year sur- vival in the known presence of tumor tissue on the aorta may not be attributed to some response to deep x-ray therapy. The possibility that the pregnancy pro- voked growth of a quiescent tumor should be considered. We are unable to provide an answer to this question.
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