Adrenocortical Carcinoma With Virilism in an Infant Under 1 Year of Age
Capt John D. Cooper, MC, USA; Lt Col Leonard Maldonado, MC, USA; and Maj Jerry M. Earll, MC, USA, El Paso, Tex
ADRENAL HORMONE producing neo- plasms in infancy are rare; however, the lim- ited literature reflects a poor, but by no means hopeless, prognosis.1,2 Only one case of virilism due to adrenocortical carcinoma, with surgical cure, has been reported in an infant under 1 year of age.3 This paper de- scribes a virilized infant with adrenal corti- cal carcinoma who is presumptively cured after surgical excision of the tumor.
Report of a Case
A 101/2-month-old white female was admitted to William Beaumont General Hospital on April 14, 1964, because of pubic hair growth of one month’s duration. She was born at this hos- pital after an uncomplicated pregnancy. The birth weight was 2.9 kg (6 lb 4 oz) and she was judged to be a normal infant. Routine examina- tions at 6 weeks and 3 months revealed normal growth and development. At 91/2 months of age, growth of pubic hair began, and medical advice was sought one month later. The past medical history and family history were non- contributory.
Physical Findings .- Examination on admis- sion revealed a very muscular but healthy ap- pearing female infant who weighed 9.7 kg (21 lb 6 oz) (75th percentile) and 74.9 cm (291/2 inches tall (90th percentile). The blood pres- sure in the left arm averaged 130/85 mm mer- cury (Hg) and in the left leg 150/90 mm Hg. There was a minimal acneiform rash on the face, no striae of the skin were seen, and there was no unusual distribution of the body fat. The optic fundi were normal. No abdominal masses were palpable. The breast tissue was not
Received for publication Jan 16, 1967.
From the Department of Pediatrics, William Beau- mont General Hospital, El Paso, Tex. Capt Cooper is now at the Fitzsimons General Hospital, Denver, and Maj Earll at Tripler General Hospital, Hono- lulu.
This review does not imply any indorsement of the opinions advanced or any recommendation of such products as may be named by the Department of the Army.
Reprint requests to Pediatric Clinic, Pediatric Service, Fitzsimons General Hospital, Denver 80240 (Capt Cooper).
unusual and the nipple pigmentation was nor- mal. There was straight black hair 1.0 cm in length on the somewhat hyperpigmented labia majora. The clitoris was moderately enlarged, and the uterus was palpable by rectal examina- tion.
Laboratory Findings .- Initial laboratory studies revealed a leukocyte count of 10,000, with a normal differential count. The urinalysis and chest x-ray films were normal. Blood chem- ical determinations showed a serum sodium level of 145 mEq/liter; potassium, 5.1 mEq/ liter; chlorides, 100 mEq/liter; and carbon dioxide, 25 mEq/liter. Blood urea nitrogen (BUN) was 16 mg/100 ml, and protein bound iodine, 6.0ug/100 ml. Glucose tolerance test at fasting was 76 mg/100 ml; at one half hour, 157 mg/100 ml; one hour, 138 mg/100 ml; two hours, 69 mg/100 ml; and three hours, 77 mg/100 ml. A buccal smear was positive for Barr bodies. Skull roentgenograms revealed no abnormalities and the bone age was estimated as 9 months. Intravenous pyelography revealed caudal displacement of the right kidney with rotation of the superior pole laterally. Twenty- four hour urinary steroid determinations are summarized in the Table.
Hospital Course .- The marked elevation of urinary 17-ketosteroids (KS), which were not suppressed by the administration of exogenous corticosteroids, and the displacement of the right kidney strongly suggested an adrenal neo- plasm. The patient was prepared for surgical exploration by administration of 25 mg of corti- sone acetate four times a day, starting one day before operation. A laparatomy was then per- formed through a wide transverse upper ab- dominal incision. In the right suprarenal area, a 5.5 × 3.3 × 3.0-cm encapsulated mass was easily dissected free and completely removed after its venous drainage to the inferior vena cava was ligated. The left adrenal gland ap- peared to be normal.
Cortisone acetate, 25 mg intramuscularly every six hours, and intravenous fluids were ad- ministered for three days after the operation; thereafter the cortisone was rapidly decreased and was discontinued on the fifth postoperative day. During the postoperative period, the blood pressure steadily declined from 130/80 mm Hg
Urinary Corticosteroids*
| 17-KSt | 17-Hydroxy- corticoidst | |
|---|---|---|
| Baseline | 12.8 | 1.3 |
| After suppression with dexamethasone, 0.5 mg every 6 hr for 3 days | 14.9 | |
| 1.8 | ||
| After stimulation with 20 units ACTH gel for 2 days | 46.0 | - |
| After operation | ||
| 1 mo | 1.2 | 0.3 |
| 2 mo | 0.5 | 0.5 |
| 6 mo | 0.8 | 0.2 |
| 9 mo | 0.5 | 0.4 |
| 12 mo | 0.7 | 1.1 |
| 30 mo | 1.0 | 1.2 |
* Pregnanetriol was normal in all specimens.
Normal values for 17-KS are 0 to 2; those for 17- hydroxycorticoids are 0.5 to 3.5; values for both are in mg/24 hr.
on the day preceding the operation to 100/60 mm Hg on the day of discharge. On the ninth postoperative day, while the patient was on re- placement therapy, a 24-hour urine determina- tion revealed 17-KS of 1.2 mg and 17-hydroxy- corticoids of 0.3 mg.
Pathological Findings .- Gross .- The surgical specimen consisted of a globular mass of tissue weighing 33 gm. There was a smooth intact capsule and the tumor was rubbery in consist- ency. On cut section, the tissue was light tan in color with small areas of yellow discoloration beneath the capsule. No areas of hemorrhage were present.
Microscopic .- Sections taken from numerous areas of the tumor revealed a few remnants of normal-appearing adrenal cortical tissue next to the thin capsule. The remainder of the mass consisted of sheets of anastomosing cords of very large cells with abundant deeply eosino- philic cytoplasm. There was considerable varia- tion in size and shape of the nuclei, with many bizarre hyperchromatic multinucleated cells to be seen. Many mitotic figures were present, both normal and abnormal. There was no definite evidence of capsular or blood-vessel in- vasion. The pathologic diagnosis of adrenal cor- tical carcinoma was verified by the Armed Forces Institute of Pathology (No. 1134153).
Follow-Up .- The patient has been observed for 21/2 years since operation and remains clini- cally well. Urinary steroid determinations have all been normal and are summarized in the Ta- ble. The blood pressure has averaged 100/60 mm Hg. Height, weight, and development have progressed in a normal pattern. There is no fa- cial acne. Pubic hair is now absent and the cli- toris appears normal for her age. Intravenous pyelography was normal six months and two vears after operation.
Comment
Adrenal cortical tumors may produce a wide variety of clinical signs and symptoms depending upon their secretory activities. The clinical picture may range from classic Cushing’s syndrome to virilism alone. Pri- mary aldosteronism has been reported in a 3-year-old child with an adrenal tumor.4 Adrenal carcinomas often present a mixed clinical picture. Our patient manifested clear signs of increased and androgenic stimulation: pubic hair, enlarged clitoris, pronounced muscular development, and ele- vated 17-KS. The hypertension and mild hypernatremia suggest salt retention or min- eralocorticoid excess and high desoxycortico- sterone secretion rates have been reported in patients with adrenal tumors.5 Evidence of excessive glucocorticoids was lacking as the infant had no unusual distribution of body fat and no abnormality of glucose metabo- lism or 17-hydroxycorticoid excretion. The observation of a normal contralateral adren- al gland and the uncomplicated rapid dis- continuation of steroid therapy in the post- operative period lend further support to this assumption.
The primary problem of differential diag- nosis lay in distinguishing between a viriliz- ing adrenal neoplasm and congenital adrenocortical hyperplasia. Signs and symp- toms of adrenal virilization present at birth are nearly always associated with hyper- plasia.6 Adrenal neoplasms have not been associated with abnormalities of sex dif- ferentiation at birth but may cause vir- ilization at any time during childhood .? Urinary pregnanetriol levels are usually ele- vated in congenital adrenal hyperplasia and are usually normal in neoplasms. Of even more importance is the easy suppression by dexamethasone of urinary pregnanetriol lev- els associated with hyperplasia. Adrenal neoplasms associated with virilism are usu- ally not brought to normal levels by the administration of dexamethasone. In tu- mors a large proportion of the 17-KS is usu- ally composed of dehydroepiandrosterone, though this was not measured in our patient. Malignant tumors in which exogenous ste- roids suppress the 17-KS to less than 50% of the high initial levels do occur,8 but it must be pointed out that even if reduction of the
initial very high levels by more than 50% occurs, there is still a high level of 17-KS production. In contrast, suppression is much more successful in congenital hyperplasia. Tumors frequently do not respond well to adrenocorticotrophic hormone (ACTH) stim- ulation, but our patient’s adrenals responded well, emphasizing that the 17-KS response to ACTH in carcinoma is variable and thus cannot be relied upon in differential diag- nosis. Radiologic examination is useful in demonstrating an adrenal neoplasm, and in- travenous pyelography will often reveal uni- lateral displacement of the renal structures. Presacral carbon dioxide insufflation is fre- quently of assistance in outlining the ad- renal glands in children.9 We did not feel the need to do this test because of the posi- tive intravenous pyelograms. Adrenocortical malignancy has been noted at autopsy in newborn infants, and it has been suggested that embryonic rests of these anaplastic cells could give rise to the masculinizing adrenal carcinomas of childhood.10 Though the his- tologic classification of adrenal tumors into benign or malignant categories is frequently difficult, there is a high incidence of ma- lignancy associated with functioning adrenal tumors in childhood.
The prognosis for an infant with an ad- renal tumor is poor regardless of its histo- logic pattern. Patients with such tumors have severe metabolic and electrolytic dis-
turbances as well as high susceptibility to infections. They may die immediately after operation, in spite of a technically successful surgical procedure and appropriate steroid and electrolyte management.8,11,12 The in- fant whose clinical picture is primarily one of virilization probably carries the best prog- nosis since he has less complicated disturb- ances of his body physiology. Preoperative and postoperative administration of exoge- nous cortisol in cases of adrenal neoplasm has been well reviewed.7,13 In patients pre- dominantly presenting with virilization, with no findings of abnormal glucocorticoid me- tabolism, corticosteroid management may be unnecessary as no pituitary ACTH suppres- sion would be expected, and contralateral adrenal atrophy should not occur.
Summary
A 101/2-month-old female infant with viril- ism secondary to an adrenocortical carcino- ma is presented. This is a rare problem in children less than 1 year of age. The tumor was successfully removed by surgical opera- tion and the virilism subsequently disap- peared. There has been no evidence of re- currence or metastasis in the 21/2 years since operation. The importance of early diag- nosis and definitive therapy is emphasized and the problems associated with diagnosis and management are briefly discussed.
References
1. Sobel, E.H., et al: Functioning Adrenal Tumors in Childhood, Amer J Dis Child 86:733, 1953.
2. Goldstein, H.M .: Cushing’s Syndrome Due to Tumor of the Adrenal Cortex: Report of a Case of an 11-Month-Old Infant With Apparent Operative Cure, Amer J Dis Child 78:260, 1949.
3. Goldstein, A.E .; Rubin, S.E .; and Askin, J.A .: Carcinoma of Adrenal Cortex With Adrenogenital Syndrome in Children: Complete Review of the Lit- erature and Report of a Case With Recovery in a Child Eight Months of Age, Amer J Dis Child 72:564, 1946.
4. Cavell, B .: Primary Aldosteronism Due to an Adrenal Adenoma in a Three Year Old Child, Acta Med Scand 174:1, 1963.
5. Crane, M.G., and Harris, J.J .: Desoxycortico- sterone Secretion Rates in Hyperadrenocorticism, J. Clin Endocr 26:135, 1966.
6. Bongiovanni, A.M., and Root, A.W .: The Adre- nogenital Syndrome, New Eng J Med 268:1283, 1963.
7. Wilkins, L .: The Diagnosis and Treatment of
Endocrine Disorders in Childhood and Adolescence, ed 3, Springfield, Ill: Charles C Thomas, Publishers, 1965.
8. Dahl, A.J., and Bastrup-Madsen, P .: Adreno- genital syndrom forarsaget af binyrebarkkarcinom hos et spaedbarn, Ugeskr Laeg 125:326, 1963.
9. Hinman, F., Jr .: Adrenal Disorders of Child- hood in Symposium of Pediatric Urology, Pediat Clin N Amer 2:889, 1955.
10. Sherman, F.E .; Bass, L.W .; and Fetterman, G.H .: Congenital Metastasizing Adrenal Cortical Carcinoma Associated With Cytomegaly of the Fe- tal Adrenal Cortex, Amer J Clin Path 30:439, 1958.
11. Gelli, G., and Della Santa, L .: Cushing’s Syn- drome in Early Infancy, Minerva Pediat 11:1389, 1959.
12. Davies, D.M .: Cushing’s Syndrome in a Child 21/2 Years, Proc Royal Soc Med 46:307, 1953.
13. Puzynsky, D.L., and Biehusen, F.C .: Adreno- cortical Adenoma With Cushing’s Syndrome and Virilism in a 5-Year-Old Child, J Pediat 60:836, 1962.
Amer J Dis Child-Vol 113, June 1967