VIRILIZING ADRENOCORTICAL CARCINOMA IN A 19-MONTH-OLD FEMALE1
MATTHEW M. STEINER, M.D.
INTRODUCTION
A DRENOCORTICAL carcinoma in a 19-month-old female is of suffi- cient interest and unusual occurrence to stimulate a report of this patient (1-6). Elaboration of excessive androgenic hor- mone resulted in a syndrome of mascu- linization with accelerated growth and skeletal maturation. Methods of dif- ferential diagnosis, including retroperi- toneal pneumography, together with problems of pre- and postoperative man- agement because of contralateral adrenal atrophy, are presented with a general discussion of virilization in the young female.
CASE REPORT
L. T., a 19-month-old white female, was admitted to the Children’s Memorial Hospital on March 2, 1955, because she had developed pubic hair and enlarged clitoris about 3 months prior to hospitali- zation. There were no other pertinent complaints except that she had a raven- ous appetite and appeared large for her age; there was no special craving for fluids, salt and sugar. She was the first born, delivered at term spontaneously after an uneventful pregnancy, weighed 6 pounds 8 ounces, and measured 21 inches in length. Nothing unusual was noted at birth, and the mother reported that the genitalia were normal until about 16 months of age. She sat up at 6 months, stood alone at 10 months, and walked at 12 months of age. The first tooth erupted at 6 months and she spoke single words at 1 year. The weight at one year was 20 pounds. A younger brother, age 5 months, appeared normal in growth and development. The father,
age 33, and the mother, age 26, were well and appeared normal in development. There were no endocrine disturbances in either side of the family.
On physical examination, she was a large, muscular 19-month-old white fe- male who walked well, played with toys actively, and was alert and cooperative (fig 1). She weighed 27 lb. 12 oz. and she was 43 inches tall (Height Age, 23 months). There was nothing unusual about the head. The fundi appeared normal, the pupils reacted to light and accommodation, and the extra-ocular muscles were intact. There were a few comedones and an acneiform eruption about the nose and cheeks. She had 16 well-formed deciduous teeth. The thyroid gland was not enlarged and there were a few small non-tender cervical glands. The apocrine activity of the axillary glands was definitely increased but there was no axillary hair. The con- tour of the chest was normal. The breasts were not enlarged but the areolae were pigmented. The lungs were clear and the heart was normal. The blood pressure was 110/60 mm.Hg. The liver extended 6 cm. below the costal margin in the right mid-clavicular line; the con- sistency was not unusual and the surface was smooth. Above an easily palpated right kidney, there was a smooth, firm, round, non-tender mass discrete from and extending under the smooth edge of the liver. The mass measured about 3 by 5 cm. and extended into the right flank (outlined in fig. 1). The external genitalia were typically female but the labia majora were prominent and hyper- pigmented. Long, black adult-type pubic hair was evident, and the hypertrophied clitoris measured 2.5 by 1 cm. (fig. 2). The external urethral orifice was at the usual female site just anterior to the vaginal opening. The hymen and introi-
1From the Department of Pediatrics, Northwestern Uni- versity Medical School. Received for publication, De- cember 5, 1956.
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tus were normal in location and appear- ance. No abnormal masses were pal- pated on rectal examination, and the internal genitalia were not unusual on bi-manual palpation. The extremities were normal and there were no abnormal neurological findings.
Results of laboratory procedures are listed in Table I. Routine blood counts and urine tests were normal. A Thorn test was normal. No abnormalities were noted on Roentgen examinations of the skull (sella), chest and long bones. There were 6 carpal centers in the wrist (Bone Age, 4 years). (fig. 3). On a flat film of the abdomen, there was a soft tissue mass in the right upper quadrant harboring irregular calcified areas. On intravenous pyelograms, the right kidney was depressed by a suprarenal mass, but both kidneys excreted the dye well (fig. 4). On the extraperitoneal pneumo- gram, obtained by presacral air insuffla- tion, a large extraperitoneal mass with calcified areas was outlined at the upper pole of the right kidney. The adrenal gland above the left kidney appeared smaller than normal (fig 5). Estimations of 24-hour urinary 17-ketosteroid excre- tion were obtained both before and after Cortisone administration. These results as well as those following surgical re-
moval of the tumor are listed in Table II.
Surgery was performed on March 9, 1955. Because of the probability of con- tralateral adrenal atrophy in the presence of a hormonally active adrenal tumor, the patient received Hydrocortisone and glucose in saline solutions intravenously both 48 hours before and during removal of the tumor, and for a varying period postoperatively. Under endotracheal an- esthesia, the left adrenal gland was first explored and was found to be very atrophic! The right adrenal tumor was then dissected free from the surrounding structures. It was a huge lobulated but well-encapsulated tumor, and its dis- section was facilitated by the presacral air insufflation. The renal vein was identified, coming very close to and send- ing off a short branch into the tumor. There was a very large vein in the super- ior portion of the tumor coming directly from the vena cava which was divided beween sutures. An artery of less than 4 mm. in diameter extended from beneath the vena cava to enter the tumor; it then appeared nearby and continued poster- iorly toward the kidney, which had been dissected free from the tumor. There was some doubt as to whether this was the renal artery, and temporary occlusion of it did not appear to alter the color of
| Glucose mg% | BUN mg% | Na Meq/L | K Meq/L | C1 Meq/L | |
|---|---|---|---|---|---|
| Before Surgery | 76 | 10 | 144.76 | 4.73 | 97.5 |
| After Surgery | 84 | 21 | 143.43 | 4.57 | 92.6 |
| Before Discharge | 57 | 12 | 148.46 | 5.09 | 99.6 |
| 17-Ketosteroid Values (mgm/24 hours) | |
| Before Surgery | 57.22 |
| After Cortisone Test | 74.21 |
| After Surgery | |
| March 10, 1955 | 17.26 |
| March 12, 1955 | 4.56 |
| Follow-Up | |
| May 12, 1955 | 4.56 |
| August 5, 1955 | 3.53 |
| December 6, 1955 | 1.88 |
| June 8, 1956 | 2.43 |
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the kidney. It was divided between ligatures as it passed into the tumor and out of it again. Gradually, it was noted that the color of the right kidney became dusky, and it was felt that this small vessel was in reality the renal artery. Ductus forceps were therefore applied on both sides of the divided artery and the ligatures were removed. The ends of the artery were freshened and end-to-end anastomosis was accomplished. After the anastomosis, pulsations in the artery were vigorous and the color of the right kidney improved. In all, the kidney was without arterial supply for about 15 minutes.
As the renal veins were being clamped, the blood pressure dropped gradually from 130/72 to 100/60 mm.Hg. During this time, the patient was receiving intravenously a solution of 10% glucose in saline with Hydrocortisone. When all the renal veins were clamped, the blood pressure fell to 80/40 mm.Hg. Whole blood and Levophed were then administered in addition to the glucose- saline-Hydrocortisone solution. The blood pressure improved gradually, and the patient withstood the removal of the tumor uneventfully. The postoperative course was stormy with hypotensive crises for which a solution of glucose in
saline with Levophed and Hydrocortisone was employed successfully. She was thus maintained on parenteral fluids until the blood pressure was stabilized, hydration satisfactory and blood electrolyte values within normal limits. Intravenous fluids were discontinued on the 4th postopera- tive day, and oral fluids and food were begun together with Hydrocortisone and liberal amounts of Vitamin C. There- after until the 16th day, Hydrocortisone was gradually discontinued. Antibiotics were administered for 14 days.
The surgical specimen measured 13 by 8 cm. and weighed 375 gm. (fig. 6). It was an ovoid well-encapsulated mass whose surface was covered by a layer of thick red to pink fibrous tissue. The tumor exhibited faint lobulation and was moderately soft and cystic. On the cut surface, there were lobules of pink-gray and red soft and friable necrotic areas separated by narrow strands of fibrous tissue. On microscopic examination, multiple sections of the tissue were com- posed of masses and sheets of cells which in some areas were grouped into lobules covered by a single layer of fibroblasts and separated by empty clefts. In other areas, these cells appeared to form no detectable pattern (fig. 7). There was marked variation in the size and shape and staining qualities of individual cells. Smaller cells, resembling those of the adrenal cortex, had large nuclei with distinct nuclear membrane and moder- ately fine chromatin granules. Other cells of the same size were present but with pycknotic nuclei and moderately abundant pale vacuolated eosinophilic cytoplasm. Numerous tumor giant cells were noted. There were many transi- tional cell forms varying in size between the two cell types. Moderate numbers of normal and abnormal mitotic figures were present (fig 8). In a few areas, notably those which were distinctly lobulated, the small cells were grouped in a pattern suggestive of the zona fasicu- lata and zona glomerulosa of the adrenal cortex. There were also a few vessels with distinct fibrous walls, and in some of these tumor cells were noted. The diag- nosis was carcinoma of the adrenal cortex.
Because of the malignancy of the tumor, deep X-Ray therapy was admin-
istered over the right upper quadrant of the abdomen and over the right lumbar region alternately each day for one month. Prior to discharge on March 25, 1955, the level of urinary 17-ketosteroids had dropped from the preoperative value of 57.2 mg. to 4.56 mg. The right kidney failed to visualize on repeated intrave- nous pyelograms. The blood pressure was 112/72 mm.Hg. Hemograms, uri- nalyses and electrolyte patterns were within normal limits. The weight on discharge was 25 pounds.
She was re-admitted in May and Au- gust 1955, for follow-up studies. The weight at the last examination was 30 pounds and she had not grown exces- sively. Pigmentation of the areolae and external genitalia was less noticeable and the pubic hair was almost gone. The clitoris was smaller and measured 1.5 by 1 cm. There were no demonstrable metastatic lesions on roentgenograms of the chest and long bones. The liver was not palpable. The level of 24-hour urinary 17-ketosteroids was 3.53 mg. The blood pressure was normal, and again the right kidney failed to visualize on intravenous pyelograms.
In a follow-up study in December 1955, there was again no evidence of metastasis and the urinary 17-ketosteroid value was 1.88 mg. The areolae ap- peared normal and there was no pubic hair. The clitoris was unchanged. In June 1956, she weighed 381/2 lb. and was 38 inches tall (Height Age, 3 yrs. 1 mo .- Chronological Age, 2 yr. 10 mo.). There was no roentgen evidence of metastasis and again the right kidney failed to visualize. Blood pressure, blood count and urinalysis were normal. The level of urinary 17-ketosteroids was 2.43 mg. per 24 hours.
COMMENT
This 19-month-old female apparently developed stigmata of virilization at the age of 16 months with enlargement of the clitoris and appearance of pubic hair. Both Height Age and Bone Age were advanced beyond the Chronological Age as evidences of somatic stimulation by excessive androgen output. Clinically, the endocrine disturbance was limited to an overproduction of androgenic sex
steroids alone since there were none of the features commonly seen in Cushing’s syndrome. The normal pattern of serum electrolytes was not altered, and the total fasting eosinophiles as well as the eosino- penic response to a standard dose of ACTH (Thorn test) was adequate.
In the differential diagnosis of virilism in a young female, it was considered that this could be the result of congenital adrenal hyperplasia with adrenogenital syndrome, adenoma or carcinoma of the adrenal cortex, as well as some of the masculinizing tumors (hilus cell or ar- rhenoblastoma) of the ovary. A large mass in the right upper abdomen, deline- ation of a suprarenal tumor by presacral air insufflation, marked excretion of uri- nary 17-ketosteroids, and the “autono- mous” nature of the tumor (absence of suppression of urinary 17-ketosteroids by Cortisone) all pointed to the diagnosis of a carcinoma of the adrenal cortex. This was confirmed at surgery and micro- scopic examination of the tumor. There was also evidence from the extraperi- toneal pneumogram that the contrala- teral adrenal gland was atrophic, which was confirmed not only by inspection at surgery but also by the marked fall in blood pressure when the renal veins were ligated. Consequently, both before, dur- ing and after surgery, Hydrocortisone and glucose in saline solutions were ad- ministered liberally to prevent and offset adrenocortical failure (7-9).
The failure of the right kidney to vis- ualize on intravenous pyelograms was probably the result of interruption of the vascular supply and consequent anoxia of the kidney. There have been no changes in blood pressure or urine, and it is not planned to remove the right kidney un- less such changes do occur. Striking reduction in the excretion of urinary 17-ketosteroids occurred soon after re- moval of the tumor, and the level has remained low in subsequent examina- tions. Associated with this diminution in androgen output, there has been striking disappearance in clinical viril- ism, e.g., pigmentation of areolae, acne and comedones, pubic hair, and promi- nence of the clitoris. Neither has there been any clinical or roentgenographic evidence of metastasis despite the pres- ence of tumor cells within the larger
vessels of the tumor. While it is still too early to determine the beneficial effect of deep X-Ray therapy in this patient, the low level of urinary 17-ke- tosteroids is considered favorable, for the occurrence of metastases is generally heralded by an increase in the output of 17-ketosteroids. However, the progno- sis in this patient remains guarded.
DISCUSSION
Three types of steroid hormones are elaborated by the adrenal cortex: 1) Anabolic or sex steroids (corticosexual) which are characterized by androsterone and such other hormones with andro- genic or progestogenic activity. Over- production of this type of hormone pro- duces masculinization in the female, and excess masculinization or at times even feminization in the male. 2) Antiana- bolic steroids or glucocorticoids (corti- cometabolic) which are characterized by hydrocortisone and cortisone. Over- production leads to hypergluconeogene- sis with loss of protein, impaired glucose tolerance, increased fat deposition with “moon face,” purplish striae, osteoporo- sis, polycythemia and eosinopenia. 3) Electrolytic steroids or mineralocorti- coids which are characterized by aldo- sterone. Overproduction leads to reten- tion of sodium, increased excretion of potassium, retention of water and hyper- tension.
Many factors influence the nature of clinical manifestations of hyperadreno- corticism or abnormal overproduction of hormones of the adrenal cortex. Whether the clinical picture is one of adrenogenital syndrome or Cushing’s syndrome, or various combinations of these syndromes, the developmental pattern is influenced by the type or combination of hormones which are overactive, as well as the age and sex of the patient at the time of overactivity.
The adrenogenital syndrome includes those patients with congenital adrenal hyperplasia which in females produces the clinical syndrome known as pseudo- hermaphroditism. This syndrome may begin in utero, and the infant at birth presents the problem, “the sex is difficult to determine.” The enlarged clitoris resembles the male phallus, there is a
perineal urethral orifice leading into urogenital sinus, and a bifid scrotum in which no testes are palpable. Bartter and his group (10) in 1951 postulated the sequence of events in the pathologic physiology of adrenogenital syndrome associated with congenital adrenal hyper- plasia. This was later elaborated upon by Jailer and his associates (11, 12), by Bongiovanni and Eberlein (13, 17), by Reifenstein (16), and many others (10- 17). There is now considerable evidence of inadequate production of 17-hydroxy- cortisone (Compound F) by the adrenal cortex resulting from a block in the con- version of 17-alpha-hydroxyprogesterone and/or 21-desoxy-hydrocortisone into 17- hydroxycortisone. Because of this defect in steroidogenesis of Compound F, there is an increased production of the anterior pituitary adrenocorticotropic hormone (corticotropin). The increased corti- cotropin then stimulates the adrenal cor- tex to produce excess 17-alpha-hydroxy- progesterone or 21-desoxy-hydrocortisone or unidentified androgenic steroids. The increased accumulation of these steroids results in an increased urinary excretion of its metabolites, particularly pregnane- triol and neutral 17-ketosteroids. More- over, the increased amounts of these ad- renal steroids results in an increase of endogenous androgens which bring about the characteristic masculinization of the adrenogenital syndrome.
The syndrome of female pseudoher- maphroditism may manifest itself later in a child apparently normal at birth with respect to the external genitalia and without evidence of a urogenital sinus. In these patients there is also progressive enlargement of the clitoris, prominence of the labia, pubic hair and increased somatic and skeletal matur- ation. Here, too, this disturbance may also be the result of congenital adrenal hyperplasia with increased excretion of 17-ketosteroids.
In the adrenogenital syndrome there is generally a predominence of the corti- cosexual group of corticosteroids, while the mineralo- and glucocorticoids are not altered. However, various dis- turbances of the mineralo- and glucocor- ticoids may occur. There are reports of adrenogenital syndrome in newborn in- fants who develop adrenocortical insuffi-
ciency with shock, cyanosis, hypogly- cemia, hyponatremia and hyperkal- emia (18). Hypertension with congeni- tal adrenal hyperplasia and pseudo- hermaphroditism has been described in an 81/2-year-old female (19, 20); among the C 21 ketonic steroids isolated from the urine of this patient were tetrahydro- S and tetrahydro-desoxycortosterone, the latter considered to be responsible for the hypertension in this patient.
When the adrenogenital syndrome is associated with overactivity of the corti- cometabolic hormones, varieties of Cush- ing’s syndrome may develop depending upon the degree of androgenic stimula- tion. Thus the degree of virilization may vary from defemininization or pseudo- masculinization with amenorrhea and hirsuitism to definite voice changes with enlargement of the clitoris. These changes are associated with the classic picture of Cushing’s syndrome which features mus- cular weakness, fatigue, hypertension, buffalo obesity, purplish cutaneous striae, easy bruisability, “moon face,” eosino- penia, insulin resistance due to impaired carbohydrate tolerance, hypopotassemia and alkalosis.
In the young female, carcinoma of the adrenal cortex usually manifests itself with signs of virilism in a child apparent- ly normal at birth with respect to the external genitalia. Again, depending upon the relative activity of the hor- mones elaborated by the carcinoma, the patient may only exhibit external signs of masculinization as presented in this report. Or, various types of Cushing’s syndrome may be produced as reported in the review by Guin and Gilbert (21-23). Methods of differentiating be- tween benign and malignant tumors have been suggested from recent investiga- tions (24-26). In adrenogenital syndrome due to congenital adrenal hyperplasia or benign tumor, values for urinary 17- ketosteroids may be normal or moder- ately elevated; in those due to malignant tumor, the values are as a rule markedly elevated. In the “pure” Cushing’s syn- drome, values for urinary 17-ketoster- oids may be normal or moderately ele- vated as in adrenal hyperplasia or benign tumor depending upon the intensity of androgenic stimulation. In virilism re- sulting from hilus cell tumor of the ovary,
the level of 17-ketosteroid excretion is largement and pigmentation of the labia, likewise not markedly elevated.
A “cortisone test” has been proposed and markedly increased excretion of (27) as a diagnostic aid in the differentia- urinary 17-ketoseroids.
tion of adrenal hyperplasia from adrenal A tumor of the right adrenal and neoplasia. In patients with bilateral ad- atrophy of the left adrenal gland were renal hyperplasia, the level of urinary outlined on an extraperitoneal pneumo- 17-ketosteroids is reduced following the gram with presacral air insufflation. A administration of suppressive doses of carcinoma of the adrenal cortex was con- cortisone, while in those with adrenal sidered because of the development of carcinoma the output of these steroids virilization in a child who was normal at does not change; the adrenocortical birth, palpation of a large tumor in the tumor is then said to be “autonomous.” supra-renal region, marked excretion of
Many recent studies have demon- urinary 17-ketosteroids, and failure of strated a persistent elevation of the uri- suppression of levels of urinary 17-ketos- nary and plasma 17-hydroxycorticos- teroids by cortisone (“cortisone test”) as teroids and the urinary 17-ketosteroids an indication of the “autonomous” na- after ACTH stimulation in patients with ture of the tumor.
adrenocortical carcinoma (24,26); in con- Following removal of the carcinoma, trast, the response has been variable or there has been loss of pubic hair, decrease absent in those with adrenocortical hy- in size of the clitoris and fall of levels of perplasia or benign tumors. urinary 17-ketosteroids to near normal
Apart from Cushing’s syndrome, virili- values.
zation of the female may be produced by Methods of differential diagnosis to- a lesion in either the adrenal cortex or gether with problems of pre- and post- the ovary. If a dramatic fall in the ex- operative management in view of con- cretion of 17-ketosteroids is brought tralateral adrenal atrophy have been pre- about by suppressive doses of cortisone, sented with a general discussion of viri- the causative pathology is presumed to lization in the young female.
be bilateral adrenal hyperplasia. In the absence of a response to cortisone, either a tumor of the adrenal or the ovary may be responsible for the masculinization. Radiographic procedures have been suc- cessfully employed in such situations, notably pneumoperitoneum and extra- peritoneal pneumography (28-31). Pneu- moperitoneum is a simple and relatively safe procedure, and the resultant outline of the ovaries can be most helpful in the differential diagnosis. Radiographic vis- ualization of the adrenal gland by extra- peritoneal pneumography by means of pre-sacral air insufflation has been a most useful procedure not only in defining the site of the tumor but also in detecting contralateral atrophy of the adrenal gland.
SUMMARY
Virilization in a 19-month-old white female resulting from a carcinoma of the adrenal cortex has been described. The symptoms began at the age of 16 months, and were characterized by enlargement of the clitoris, growth of pubic hair, en-
increased height and skeletal maturation,
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