Virilizing Adrenocortical Carcinoma Development in a Patient With Salt-Losing Congenital Adrenal Hyperplasia
Arthur Bauman, MD, Caroline G. Bauman, MD
CONGENITAL adrenal hyperplasia (CAH) is an uncommon disorder, but the incidence of virilizing adrenocor- tical neoplasms, benign and malig- nant, is even less common.’ The occur- rence of both conditions in the same patient25 raises the question of whether or not the association is coincidental.
The patient described herein was born with a salt-losing form of CAH, probably caused by a severe 21- hydroxylase deficiency; despite ade- quate control, a virilizing carcinoma of the adrenal cortex developed.
Report of a Case
An 11-year-old girl was admitted to the White Plains (NY) Hospital Medical Cen- ter because of progressive virilization associated with strikingly increasing lev- els of urinary 17-ketosteroids (17-KS).
During the first week of life, the patient had had persistent vomiting, weakness, and convulsions. Serum sodium level had been 126 mEq/L, and serum potassium level, 9.2 mEq/L. The clitoris had been enlarged and the labia majora fused. A cystourethrogram had shown dye in a vaginal pouch and uterine cavity, both posterior to the bladder. A salt-losing form of CAH had been diagnosed, and the child’s designated gender changed to female.
Treatment with cortisone; desoxycorti- costerone acetate, and intravenous (IV) saline solution had produced dramatic improvement, with restoration of electro- lyte values to normal. Cortisone therapy, 10 mg orally. daily, had reduced the 24- hour excretion of 17-KS from 11.2 to 1.7 mg (normal, <1 mg for an infant [per- formed by Bioscience Laboratories, Van Nuys, Calif]).
The patient had been given cortisone for eight months, then .hydrocortisone; the 24-hour urinary excretion of 17-KS had remained between 3:9 and 5.8 mg through- out her childhood. Bone age had been
From the Section of Endocrinology; Department of Medicine (Dr A. Bauman), and the Department. of Pediatrics (Dr C. G. Bauman), White Plains (NY) Hospital Medical Center.
Reprint requests to 115 Davis Ave, White Plains, NY 10605 (Dr A. Bauman).
normal at 17 days of age and at ages 6 and 10 years but had notably advanced during the last stages of her final illness, when urinary 17-KS excretion was inordinately elevated and uncontrolled. She had also received liberal quantities of sodium chlo- ride in her diet, and substantially. more hydrocortisone plus an electrocorticoid (deoxycorticosterone or : 9a-hydrocorti- sone) had been required periodically for adrenocortical crises associated with childhood illnesses.
At 10 years of age, there had been an abrupt growth spurt. The patient’s accel- erated rate of growth had moved her up from the 10th percentile to the 50th per- centile within a few months, paralleling a striking increase in 17-KS production. Whereas 17-KS excretion had previously been 5.8 mg/24 hr or less,. it had risen progressively from 20 mg/24 hr to 200 to 402 mg/24 hr within eight months. When the total 24-hour urinary excretion of 17-KS had been 187 mg, the 11-desoxy fraction had accounted for 102 mg. There had been 75 mg of dehydroepiandroste- rone, 8.5 mg of etiocholanolone, and 18.5 mg of androsterone, but a total of only 6.3 mg for the 11-oxy group of compounds. Dexamethasone, 3. and 16 mg/24 hr, had failed to suppress 17-KS excretion. Corti- cotropin, 25 units IV during a four-hour period, had failed to stimulate. total 24- hour urinary excretion of 17-KS. Metyra- pone, 0.75 g every six hours for :12 doses, had not increased the 24-hour urinary excretion of 17-KS, which might have occurred had metyrapone stimulated the seeretion of . the 11-oxy compounds of androsterone and etiocholanolone sub- stantially. Estrogen secretion had been elevated, with 24-hour urinary excretion of total estrogens at 55 ug (reference value before puberty, <4 ug+): 41 ug of estrone, 2 ug of. estradiol, and 12 ug of estriol. Pregnanetriol excretion had been 12 to 24 mg/24 hr (reference value in this age group, <2 mg/24 hr6).
Physical examination on admission to our hospital disclosed a virilized youngster with an abundance of coarse, black hair. on the face, anterior part of the chest, and extremities. A male escutcheon was pres- ent. There was considerable acne on the face and upper part of the thorax. No breast development was noted. There were fullness and pain in the left upper quad-
rant and epigastrium.
At surgery, a 1,650-g tumor was removed with the left adrenal gland. Hepatic metastases were noted. Adminis- tration of: mitotane, 6 g daily, had no effect on the clinical course. The 17-KS excre- tion, which had fallen to 24 mg/24 hr immediately after surgery, rose to 340 mg/24 hr.within two months. The patient subsequently went into shock and died of a massive hemorrhage from necrotic hepatic metastases.
Pathological Findings .- The tumor weighed 1,650 g; the capsule was firm, and areas of necrosis were seen throughout. Microscopic examination disclosed large areas of necrosis alternating with better- preserved tissue. The cells were polygonal, with distinct borders. and prominent but varying-sized nuclei and clumping within a distinct nuclear membrane. The cyto- plasm was noticeably eosinophilic. Multi- nucleated giant cells were. prominent and nucleoli were present. Mitotic figures were occasionally seen among the polygonal cells, which were divided into groups of various sizes, separated by delicate strands of fibrous tissue and vascular channels. Foamy macrophages in groups were scattered among the tumor cells. Tumor cells invaded and extended through the capsule and were present in some vascular channels. The diagnosis was viril- izing adrenocortical carcinoma of the left adrenal gland.
Autopsy Findings .- The lungs weighed 650 g and were studded with innumerable tumor nodules. Tumor nodules surrounded the abdominal aorta. The liver weighed 340 g, and tumor masses, many of which were hemorrhagic and necrotic, were found on the surface and throughout the hepatic parenchyma. Tumor tissue was also noted in the pancreas and upper pole of the left kidney. There was a massive · amount. of blood in the peritoneal cavity. Microscopically, tissue from all areas resembled the tissue of the previously removed primary tumor.
The right adrenal gland weighed 3 g. The cortex was bright yellow. The three layers of cortex were identified microscop- ically, but the cells in all three layers were smaller and - more tightly packed than normal. The diagnosis was metastatic vir- ilizing adrenocortical. carcinoma and atro- phy of the right adrenal gland.
Comment
Once the correct .diagnosis of a salt-losing form of CAH was made, the patient was given physiological doses of cortisol, which resulted in satisfactory growth and development and suppression of 17-KS excretion to near-normal levels.
During the final illness, masculini- zation and inability to suppress the strikingly increased excretion of uri-
nary 17-KS suggested the presence of a virilizing tumor.
In 1958, Hamwi et al2 reported. a case of adrenocortical carcinoma in a 39-year-old woman who may have had. CAH. Since virilization had started at the age of 9 years, it is unlikely that she. had had a function- ing adrenocortical carcinoma for 30 years. Bratrud and Thompson’s’ pa- tient had been virilized from early. childhood. and had had carcinoma of the adrenal gland at the age of 32 years. A hypertrophied contralateral adrenal gland also supported the diagnosis of CAH. Lynch’s” patient, . whose condition had improved on removal of a virilizing adrenocortical adenoma, had had enlarged adrenal. glands and persistently elevated 17- KS excretion, both characteristic of CAH.
Pang et al’ reported a virilizing adrenocortical tumor in a patient with CAH. Patient compliance with
glucocorticoid. therapy was poor, as indicated by persistent hyperplasia of the nontumorous part of the adrenal gland and. the contralateral adrenal gland .:
In infancy and early childhood, the diagnosis of CAH with. a 21-hydroxy- lase deficiency is usually based on ambiguous genitalia, with elevated 17-KS urinary excretion, increased concentration of precursor steroids of blocked metabolites such as serum 17-hydroxyprogesterone, and in- creased 24-hour urinary excretion of pregnanetriol, all of which are invari- ably suppressible to normal or near normal with glucocorticoids. This last criterion serves to differentiate CAH from tumor. It is not infallible, how- ever; Korth-Schutz et al6 described a 14-month-old child with these. find- ings who was treated with dexameth- asone for three years until a diagno- sis of adrenocortical carcinoma was apparent. Gregory et al’ described an
18-month-old girl in whom a viriliz- ing adrenocortical carcinoma. re- sponded to corticotropin stimulation and was partially suppressed with glucocorticoids:
References
1. Fraumeni JF, Miller- RW: Adrenocortical neoplasms with hemihypertrophy, brain tumors,. and other disorders. J Pediatr 1967;70:129-139.
2. Hamwi GJ, Serbin RA, Kruger FA: Does adrenocortical hyperplasia result in adrenocerti- cal carcinoma? N Engl J Med 1957;257:1153- 1157.
3. Bratrud TE, Thompson WH: Congenital hyperplasia of adrenals. Staff Meet Bull Hosp Univ Minn 1943;15:25-43.
4. Lynch J: Functional tumor of adrenal cor- tex of a male child. JAMA 1950;144:921-923.
5. Pang S, Becksen -D, Cotelingham J, et al: Adrenocortical tumor in:a patient with congeni- tal adrenal hyperplasia due to a 21-hydroxylase deficiency. Pediatrics 1981;68:242-246.
6. Korth-Schutz S, Levine LS, Roth JA, et al :. Virilizing adrenal tumor in a child suppressed with dexamethasone for three years: Effect of op’-DDD on serum and urinary androgens. J Clin Endocrinol Metabol 1977;44:433-439:
7. Gregory T, Gardner LI, Gower DB, et al: Studies of 16-androstenes in an infant with virilizing adrenocortical carcinoma. Am J Dis Child 1979;133:294-297.
Acute Renal Failure Secondary to Amoxapine Overdose
Andres J. Pumariega, MD; Betty Muller, MD; Noel Rivers-Bulkeley, MD
AMOXAPINE is a new antidepres- sant approved for marketing in the United States just over a year ago. It is structurally similar to both loxa -; pine succinate and imipramine hydro- chloride, and its mechanism of action. is through blocking the reuptake of norepinephrine primarily and. sero- tonin secondarily as well as having a dopamine-receptor blocking effect. It has become one of the most popular antidepressants in use today, largely because of its low incidence of side effects and toxic reactions and its possible earlier onset of action.15 Our recent experience with a patient who ingested excessive amounts of this drug has alerted us to. a yet unre- ported and potentially lethal compli- cation of amoxapine overdose.
From the Departments of Psychiatry (Drs Puma- riega, Muller, and Rivers-Bulkeley) and Pediatrics (Dr Pumariega), Vanderbilt University Medical Cen- ter, Nashville, Tenn.
Reprint requests to Division of Child & Adolescent Psychiatry, Vanderbilt University Medical Center, 243 Medical Center South, Nashville, TN 37212 (Dr Pumariega).
Report of a Case.
A 17-year-old girl was transferred to Vanderbilt University Medical Center, Nashville, Tenn, from an outlying hospital after ingesting at least 4 g of amoxapine (approximately 60 mg/kg) in an impulsive suicide gesture. She had been under psy- chiatric treatment for depression at a local mental health center, and her dose had been increased a few days before to 200 mg/day. Two and a half hours after the ingestion, she was discovered and was. rushed by her family to the local emergen- cy room. She experienced grand-mal sei- zures in the emergency room 41/2 hours after ingestion and was treated with 10 mg of diazepam intravenously (IV). Gastric lavage was then attempted, but the sei- zures recurred. Two milligrams of physo- stigmine salicylate IV and 100 mg of phenytoin IV were administered, but her seizures recurred again two hours later. An oral airway was placed, and she was given oxygen by nasal cannula. She was not noted to be cyanotic during this period, and her respiratory rate (16 to 24 beats per minute) and BP (diastolic, 66 to 90 mm Hg) were stable.
After her transfer to the pediatric intensive care unit at our hospital, her cardiac rhythm, central venous pressure, and arterial blood gas levels were closely monitored. The patient was obtunded but responded to simple commands. Her sei- zures had ceased by that point; however, on admission, nine hours after the inges- tion, her serum urea nitrogen level was 13 mg/dL; creatinine level, 2.1 mg/dL; potas- sium level, 3.3 mEq/L; and uric acid level, 18.3 mg/dL, with other electrolyte levels within normal limits. Urinalysis findings were within normal limits, with a negative test result for occult blood in her stool. A toxic (serum) drug screen collected about 11 hours after ingestion showed signs of amoxapine. The laboratory did not yet assay amoxapine levels on a regular basis. A special assay yielded a level of “less than 1.mg/L,” the lowest sensitivity avail- able .:
On the second day of hospitalization, the. patient had two generalized seizures and underwent manual ventilation with 100% oxygen on becoming briefly cyanotic. She was treated with IV phenytoin, with reso- lution of her seizures, and she continued receiving therapeutic levels for four days thereafter. However, her creatinine level had increased to 2.3 mg/dl and 3.9 mg/dL later that day and her serum urea nitro- gen level rose to 15 mg/dL. and 18 mg/dL later. Her urine output dropped to 15 to 20 mL/hr (0.25 mL/kg/hr), despite receiving 20 mg of furosemide IV at the local hospital. The patient was treated for oli-