Adrenal Cortical Carcinoma in Children

THE JOURNAL OF UROLOGY

Vol. 66, No. 4, October 1951 Printed in U.S.k

ADRENAL CORTICAL CARCINOMA IN CHILDREN ROBERT A. GARRETT

From the Department of

University School of ]VJ edicine'

With the increasing study of adrenal cortical activity in the past two decades has come a better understanding of the functioning tumors of the adrenal cortex. The more recent contributors to the literature on this subject, notably \Valters 1 and Cahill,2 are in essential agreement on a general classification of these neoplasms, based upon their clinical manifestations of hormonal activity, as follows: 1) Nonhormonal, those displaying no endocrinologic activity; 2) androgenic, those elaborating excess masculinizing steroids; 3) estrogenic, those elaborating excess feminizing steroids; 4) androgenic plus other metabolic hormones, those displaying clinical features of masculinization and Cushing's disease; 5) metabolic tumors without androgens, those displaying Cushing's disease ·without masculinization; G) metabolic tumors of one function, those manifesting one metabolic disorder. The physiology underlying the clinical behavior of such adrenal tumors is complex. The reader is directed to excellent papers on this subject by Kenyon 3 and Cahill 4 where it is discussed in detail. It is sufficient to state that the adrenal cortical steroids isolated to date are numerous and their interrelation not completely understood. There appear to be, however, three main groups functionally: 1) Those bringing about secondary sexual characteristics, viz. estrone (estrogenic) and testosterone (androgenic); 2) those concerned with regulation of electrolyte balance, viz. desoxycorticosterone; 3) those concerned with carbohydrate, protein and fat metabolism, viz. corticosterone, dehydrocorticosterone and others. The interplay between these steroids and other endocrine structures is of even greater complexity, and is the subject of intense investigation today. Thus, it is easily understood that there are numerous clinical pictures that may be displayed by these patients in whom tumor function is not clean cut and limited to one of the foregoing main groups. INCIDENCE

We will limit our discussion to the appearance of this tumor in children. During a 26 year period, 83,220 patients have been admitted to the Riley Hospital for Children. There have been 4 authenticated cases of adrenal cortical tumors, all of which proved to be carcinoma. Kumerous other children showing variations of the adrenal cortical syndrome have been studied and either proved to he suffering from cortical hyperplasia or operation to ascertain the true identity of the lesion ,ms refused. Read at annual meeting, North Central Section American Urological Association, Milwaukee, Wis., October 13, 1950. 1 Walters, W. and Sprague, R.: Ann. Surg., 129: 677, 1949. 2 Cahill, G. F., l\Telicow, M. M. and Darby, H. H.: Surg. Gynec. & Obst., 74: 281, 1942. 3 Ken 0·on, A. T.: Surgery, 16: Hl4, 1944. 'C:1l1ill, G. F.: Surgery, 16: 233, 1944. 477

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It is generally agreed that androgenic tumors with or without Cushing's syndrome are the most frequently encountered. These tumors occurring in children produce heterosexual changes in the female and isosexual changes in the male. The female child is more often affected. Those having purely metabolic features (Cushing's syndrome) are relatively rare as are those having no hormonal characteristics. The nonhormonal tumor is particularly rare among children. Estrogen-producing tumors either in male or female children are extremely rare. Cahill2 reported one such case in an adult male. DIFFERENTIAL DIAGNOSIS

Endocrine disorders arising in other sites must be excluded. As emphasized by Smith, Evans and vVarkany, 5 two other sources of endocrine disease may give rise to confusing clinical states. Cerebral lesions in and about the pineal body as well as the hypophysis may be responsible for an excess production of adrenocorticotropic hormone or gonadotropic hormones which may produce precocious or pseudoprecocious puberty and thus mimic the primary adrenal cortical syndrome. Careful study of skull bony outline may detect a central lesion responsible for the clinical picture encountered. It is also well known that neoplasms of the gonads may produce hormones behaving functionally in a similar manner. A tumor of the gonad mimicking the adrenal cortical syndrome will usually be found on palpation although they may be quite small and escape detection. Lesions of cerebral and gonadal origin having been excluded, differentiation of the lesions of the adrenal cortex may then be done in so much as is possible. Limitations in diagnosis are definite; surgical exploration may be imperative to establish the true identity of the lesion. Roentgenographic visualization of the adrenal overgrowth by perirenal air insuffiation has been employed successfully. Pyelographic studies may disclose renal displacement on the affected side. Modern methods of androgenic determination with fractionation into alpha and beta components together with estrogenic assay enable an increasingly accurate evaluation of tumor function. To these are added methods for laboratory evaluation of the electrolyte regulating, as well as carbohydrate, protein and fat regulating hormones. Determination of the 17-ketosteroids may be quite helpful. With the normal values of practically O mg. until the age of 7 years and the slow rise to adult levels from 7 years until puberty one may rather accurately detect gross androgen overproduction. Quantitative levels in the higher brackets seem to be largely the result of tumor whereas adrenal cortical hyperplasia seldom produces high levels. This is not always dependable, however. Fractionation of the ketosteroids into alpha and beta segments may give even more accurate information inasmuch as the cortical tumor produces a level composed of relatively more beta fraction than does the cortical hyperplasia. Escamilla 6 and many others have published data pertinent to this determination in clinical diagnosis. As in case 1 the 17-ketosteroid level may not be elevated, while other steroids 5

6

Smith, P. G., Evans, A. T. and Warkany, J.: J. Urol., 64: 784, 1950. Escamilla, R. F.: Ann. Int. Med., 30: 249, 1949.

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of metabolic significance may be considerably in excess of normal. Estrogen levels are elevated infrequently. Biochemical determination of the cortico-steroids, which regulate electrolyte balance, carbohydrate, protein and fat metabolism, is of value. Those patients displaying the Cushing syndrome will often show elevations of this fraction. The normal value in the child is thought to be between 0.3 and 0.4 mg. for a 24 hour urine sample. CASE REPORTS

Case l. (S.O. XR 107461.) On March 6, 1947 a 2 year old white girl was admitted to this hospital, the parents complaining that the child weighed too much, had a recent excessive hair growth over the general body surface and wet her-self at frequent intervals. The child had enjoyed normal health and development

F'rn. 1. Case 1. A, grotesquely obese 2 year old girl, preoperative. B, 2 years postoperative.

until 6 months prior to admission. At that time excessive weight gain was noted. A profusion of hair over the back, vulva and forehead made its appearance 2 months later. Acne developed 1 month prior to admission. Glycosuria and albuminuria were reported by the family physician. A prodigious appetite developed during the progression of the disease, as ,vell as a noticeably increasing irritability. The mother described progressive polydipsia accompanied by increased bed and clothes wetting. At examination a grotesquely obese child (fig. 1, A), weighing 41 pounds was seen. Coarse hirsutism over mons veneris and downy hair over the forehead, shoulders, back and legs were noted. There was a generalized facial acne. Hypertension of 180/120 was found. There were no detectable breast changes, nor was there hypertrophy of the clitoris. No masses could be palpated in the abdomen.

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Blood count: hemoglobin 11 gm., white blood count 15,850 of which 48 per cent were polymorphonuclears (no eosinophils). The fasting blood sugar on two occasions was 80 and 186 mg. per cent, total non protein nitrogen 34 mg. per cent, cholesterol 126 mg. per cent, serum potassium 22 mg. per cent (5.6 mEq.), serum sodium chloride 624 mg. per cent (106 mEq.), serum phosphorus 3.8 mg. per cent, serum calcium 13 mg. per cent and 4 plus cephalin flocculation. Survey films of the skull were normal. Ossification centers in the wrists were normal. Plain urograms on several occasions demonstrated a spherical soft tissue mass superior to the right kidney (fig. 2, A), which proved to be displacing the right kidney downward, rotating its long axis to the horizontal in the anteroposterior plane (fig. 2, B and C). The hypertension during the preoperative phase maintained its high level without wide fluctuation. Determination of the 24 hour

Fm. 2. Case 1. A, plain urogram showing spherical density above right renal outline. B, retrograde pyelogram (anteroposterior) showing downward displacement of right kidney. C, retrograde pyelogram (lateral) showing downward displacement and rotation of right kidney.

urinary 17-ketosteroid output was found to be less than 1 mg. l; nfortunately this was not repeated. Urinary estrogens and corticosteroids were not determined. On the sixteenth hospital day, the child suffered a sudden episode of cyanosis. The pulse rose to 145 and the blood pressure to 200/160. Pulmonary congestion ensued and the patient appeared to be in acute left ventricular failure. The patient's general condition improved slowly under supportive measures. A transperitoneal approach to the right adrenal was carried out on March 26. Palpation of the left adrenal gave the impression that this gland was normal. A tumor measuring 5 by 4 by 3 cm. was enucleated from the right adrenal bed. Pathologic study showed a highly cellular mass, the cells of which were polygonal and contained eosinophilic cytoplasm. Numerous mitotic figures were seen. A dense capsule embraced the neoplasm. The diagnosis of adrenal cortical carcinoma was made. The postoperative course was satisfactory. No cortical extract had been administered prior to surgery, however percortin was utilized for 24 hours immediately postoperatively. At no time did signs of adrenal cortical insufficiency develop. On the contrary the hypertension persisted steadily at 170/135. The child was discharged on the tenth postoperative day.

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One month after discharge, when seen in the follow-up clinic, the child appeared somewhat less excitable. Appetite had diminished and a weight loss of l½ pounds was noted. The blood pressure recorded at that time was 120/80. A two-year follow-up was completed on June 4, 1949. The child's weight and appearance were normal (fig. 1, B) as was the blood pressure. Case 2. (S.M. XR 11650.) A 2 year old white boy was admitted to the hospital on December 13, 1930 in a moribund state with multiple ulcerations over the extremities, abdominal swelling and the complaint of numerous nosebleeds. The child had been ill for 1 year. The first noted abnormality according to the parents was that of excessive weight gain. Examination of the child demonstrated an excess of fat over the trunk, the extremities not participating. The cheeks were full and plethoric. Body ·weight was 28 pounds. Purpuric areas noted over the body apparently were not striae. The fontanel was open. It was recorded that the genitalia were well formed. There ·were numerous ulcers over both lower extremities. An excess of hair over the body was not localized. Laboratory findings: white blood cells 4,700; red blood cells 4,600,000, bleeding time 35 minutes, clotting time 8 minutes, platelets 315,000. Differential showed 29 neutrophils, 55 lymphocytes, 1 eosinophil and 15 mononuclears. The urine was negative. No note was made of polyuria. 'Grinary hormonal studies were not done. Blood serology was negative. X-ray studies of the long bones showed delayed ossification. The child's hospital course was rapidly downhill, in spite of numerous blood transfusions. During the entire hospital stay a temperature elevation of moderate degree was recorded. Ulcerations on the extremities increased in number and size, coalescing in some areas. The child died on its fourteenth hospital day. Autopsy report: There was a disproportionately large amount of fat deposition over the trunk. ="l' umerous hemorrhagic ulcerative areas were noted over the extremities and trunk. On opening the abdomen, the spleen and liver were uniformly enlarged. A tumor mass, ·weighing 70 gm. was found in the left adrenal bed. It was spherical and brownish-yellow in hue on section. Microscopic diagnosis of this tumor was carcinoma of the adrenal cortex. Several enlarged para-aortic lymph nodes were sectioned and found to contain deposits of metastatic carcinoma. The pituitary was carefully sectioned and found to be normal. Case 3. (S.T. XR 14894.) A 4 year old girl was admitted to the Riley Hospital on December 18, 1931. The parent stated that a mass had been noted in the abdomen I½ years previously which had progressively become larger. Marked growth of the clitoris had occasioned its removal 8 months previously. Voice changes had become prominent, lowering to an adult male level. An acne had existed for many months. No breast changes were noted. Vaginal bleeding had not taken place. On examination the blood pressure was found to be 98/70. Xo note was made of obesity. The abdomen was markedly enlarged due to a tumor mass indefinitely outlined in the left flank (fig. 3). Labia were thought to be adult in size. Pubic hair was luxuriant and distributed in male fashion. Axillary hair was undeveloped.

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Laboratory studies: red blood cells 5,080,000; white blood cells 17,300 with normal differential (no eosinophils); repeated urinalyses were normal; blood total nonprotein nitrogen was 38 mg. per cent. No hormonal studies were done on the urine. Barium enema indicated gross displacement of the descending colon to the right. No metastatic deposits were found in the chest or long bone studies. A laparotomy was done January 12, 1932. A large encapsulated tumor mass 23 by 16 by 11 cm. was removed from the left adrenal fossa together with adherent overlying peritoneum. Histologically the picture was that of a highly cellular uniform mass of polyhedral cells resembling the cells of adrenal cortex. The diagnosis of carcinoma of the adrenal cortex was made.

Fm. 3. Case 3. Showing abdominal distention due to tumor and hypertrophy of clitoris.

The postoperative course of the child was characterized by hyperpyrexia. No hormonal replacement therapy was given. The blood pressure fell to shock levels in spite of blood transfusions and supportive therapy. Vomiting became severe. The patient expired 36 hours after surgery. An autopsy was refused. Case 4. (F.W.S. XR 144878.) A 12 year old boy was admitted on June 6, 1950 to the Riley Hospital with the complaints of obesity, growth of a beard and weakness. Approximately 1 year previously it was noted that the child, formerly quite extrovertive, came to prefer seclusion. He had no complaints. In January 1950, a rapid increase in weight took him to a physician who prescribed a reduction diet. At about the same time the boy began to grow a coarse black beard and pubic hair became luxuriant. These characteristics progressed unabated. In recent months fatigue and weakness became prominent. Pain in the abdomen made its appearance in May 1950. No polyuria or polydipsia was noted. The abdomen became quite distended during the 2 weeks preceding admission. Ankle edema simultaneously became pronounced. No acne has accompanied the illness. The past history was not significant. The family history was noncontributory.

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On physical examination a very obese child was seen (fig. 4). The obesity was confined to the torso ·with little extremity involvement. There was a pronounced buffalo-hump formation. The head was almost spherical. Beard on the lip and cheeks Yrns pronounced. A plethoric appearance was striking. Pubic hair was adult in distribution and quantity. Genital development approached that of an adult. ~ umerous purple striae were seen on the flanks and thighs. There was no palpable lymphadenopathy. The lungs ,cvere clear. The heart was normal to physical examination except for a moderate tachycardia of 100 beats. The blood pressure was 160/110. Abdominal examination revealed two distinct masses. One emerged from beneath the left subcostal margin to extend downward to the umbilicus and medially to the midline. It was rather immobile and painful, but

Fm. 4. Case 4. Showing typical facies of Cushing's syndrome. Note striae over thighs and legs, and adult pubic hair.

smooth. The second, presumably liver, extended 6 cm. inferior to the right subcostal margin and Yvas not nodular. The prostate, on rectal examination, was considerably larger than would be expected in a child of this age, although it was normal in all other respects. The neurological examination was negative. Blood count: hemoglobin 12 gm., red blood cells 4,250,000; ·white blood cells 10,900, bands 20, polymorphonuclears 66, lymphocytes 8, large monocytes 6. The urinalysis was repeatedly negative. The Handolph eosinophil count was 44. Blood serology for syphilis was negative. The blood nonprotein nitrogen was 31 mg. per cent. Blood sugar was 142 mg. per cent. E:erum sodium was 143 mEq., potassium was 5.7 mEq. On two occasions the urinary 17-ketosteroids ,Yere 60.5 and 51.3 mg. per cent. Urinary gonadotropic hormones ,Yere at a low normal level. Estrogenic hormones in the urine were found to be greater than 20 r.u. per liter. rrinary corticosteroids were elevated to 3.5 mg. Roentgenographic survey included normal skull films. Bone age ,ms found to be normal. There was no demonstrable osteoporosis. A plain urogram and excretory urograms revealed a large spherical mass in the left upper quadrant, stippled with amorphous calcific

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deposits, displacing the left kidney downward and laterally. Aside from gross displacement the pyelograms were normal. The preoperative phase was uneventful. The child preferred to remain in bed most of the time. On June 22, 1950 a thoraco-abdominal approach was utilized. The large retroperitoneal mass, seemingly encapsulated yet quite fixed, was seen displacing the splenic flexure of the colon downward. Liver palpation disclosed three metastatic nodules varying from 5 to 15 mm. in diameter in the left lobe of the liver. It was felt futile to remove the primary tumor mass, so biopsy was taken and the abdomen closed in layers with silk sutures. The pathologic study showed solid sheets of polygonal cells having pink staining granular cytoplasm. There was considerable variation in nuclear size and staining properties although few mitoses were seen. Adrenal cortical carcinoma was advanced as the histologic diagnosis. A trial of abdominal radiation 1 week after surgery precipitated increasing dyspnea and cyanosis. This was discontinued after little tumor response. vV ound healing was slow and indolent. A downhill course characterized by increasing dyspnea, abdominal pain and loss of appetite terminated in death on September 3, 1950. No postmortem examination was obtained. DISCUSSION

In attempting clinical classification of these cases, all but case 2 are susceptible of clean cut disposition. The presence of obesity, hypertension, hirsutism and acne without virilism in case 1 points to the pure Cushing's syndrome. The absence of 17-ketosteroid elevation in this child further strengthens this classification. Presence of the Cushing's syndrome with precocious virilism and elevation in the ketosteroid and corticosteroid levels place case 4 in the class of tumors displaying metabolic and androgenic features. Case 3 may be placed in the purely androgenic group in the presence of marked masculinization with absence of obesity and hypertension. The excessive body hair and obesity in case 2 suggests a purely metabolic tumor displaying Cushing's syndrome. However, the terminal state of this child and the incomplete workup make such a disposition questionable. Many facets of hormonal imbalance are displayed by these cases. As is not infrequently found, the presence of excessive androgen and estrogen was found in case 4. Undoubtedly estrogenic effect was blanketed by a proportionately stronger androgen activity. Hyperglycemia was noted twice (cases 1, 4). This insulin resistant type of hyperglycemia is thought to be the result of excessive gluconeogenesis initiated by the hypercorticism. The presence of hypertension (cases 1, 4) is mediated by an uncertain mechanism. It is interesting to note the persistence of hypertension for at least 10 days after complete removal of the tumor in case 1. vVe misinterpreted this fact to indicate distant functional metastases. The urgency of surgery in the pronounced hypertensive patient is illustrated in case 1, where acute cardiac failure supervened, and was corrected only with difficulty. While it is well knmvn that sodium and potassium metabolism are directly influenced by adrenal cortical activity it is notable that serum liwels of these electrolytes are infrequently abnormal in adrenal cortical tumors.

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Aberrations in electrolyte balance in such cases are best detected by sweat and urine excretion values. Polyuria, a primary complaint in case 1, is apparently due to direct action of an adrenal cortical diuretic substance upon renal tubular epithelium. The overproduction of this hormone, normally acting in balanced interplay with pituitary antidiuretic hormone, upsets water balance. 7 X-ray studies may be decisive in diagnosis. Pyelographic studies disclosed renal displacement in cases 1 and 4. The mass may be quite visible on flat plate of the abdomen (cases 1, 3, 4). The transperitoneal approach to the adrenal through a transverse abdominal incision has seemed satisfactory in our hands. It allows simultaneous exposure of both adrenals through one incision as well as general visceral palpation for metastases. An exceptionally large tumor may be exposed to advantage the combined thoraco-abdominal approach (case 4). Postoperative management is of vital importance, particularly in those children displaying Cushing's syndrome. Acute adrenal insufficiency may occur after removal of these tumors (case 3). Frequently partial atrophy of the contralateral adrenal may co-exist. Thus, transitory insufficiency until resumption of full function of the atrophic gland may be adequately handled with the judicious use of adrenal cortical extract, desoxycorticosterone acetate and saline infusions. Prognosis depends to a great extent upon the type of tumor encountered.Nonfunctional tumors, of course, often manifest themselves by mass alone. This is frequently too late for surgical extirpation. Simple estrogenic and androgenic tumors are susceptible of early detection. Their surgical removal is seldom accompanied by acute adrenal insufficiency, although this apparently occurred in case 3. Those tumors having "cushingoid" characteristics while often discovered early, may have a fatal outcome if acute adrenal insufficiency following surgery is not skillfully managed. The salvage of only one of the 4 patients here reported emphasizes the great need for early diagnosis and aggressive postoperative treatment. All three cases with fatal outcome should have been recognized earlier. Adequate postoperative hormone administration will greatly reduce the mortality attributable to adrenal insufficiency. SUMMARY

Four cases of adrenal cortical carcinoma in children are reported. A brief discussion of a classification based upon functional activity of these tumors is presented. The differentiation of these lesions from similarly functional states related to cerebral or gonadal origin must be made. The variable clinical modes of manifestation may be explained on the basis of steroid physiology. The author wishes to acknowledge with gratitude the use of "Pediatric Urology in Indiana University, Abstracts of Clinical and Autopsy Records from 1924 to Date" by Drs. H. 0. Mertz and Frank Forry, in the preparation of this paper. 7

Lotspiech, W. D.: Endocrinol., 44: 314, 1949.