Carcinoma of the adrenal gland in children

Carcinoma of the Adrenal Gland in Children By David R. Stewart,

Patricia H. Morris Jones,

and Ambrose Jolleys

T

HE ADRENAL GLAND is an uncommon site of malignant disease in children, but those tumors which do occur manifest themselves in a variety of interesting ways. Neuroblastomas represent the largest group of adrenal tumors, and their recognition and management has become fairly well established. Most reported series, however, note only small numbers of adrenocortical adenomas and carcinomas, and the depressingly low survival figures, 23 of 222 cases, cited in a recent review of the literature’ are in part attributable to the lack of familiarity with the disease. Most of these endocrine tumors are functionally active, producing Cushing’s syndrome, virilization, feminization, or a combination of these features. Aldosteronomas of the adrenal cortex produce hypertension only, a few of the tumors may produce hypoglycemia only, and a small number of adrenocortical tumors are nonfunctional. This latter group occurs particularly in males. MATERIALS

AND METHODS

During the past 20 yr 141 infants and children with neoplasms of the adrenal gland have been seen in the Manchester region. Of these neoplasms, 130 were neuroblastomas and the rest included functioning and nonfunctioning adrenocortical carcinomas and three phcocbromocytomas. The five children with functioning adrenocortical carcinomas form the basis of this presentation. In each case, the diagnosis of adrenocortical cancer was established by a review of the histologic sections and clinical presentation by the panel of pathologists of the Manchester Tumour Registry. Follow-up data are available in all five cases. The following methods were used for biochemical determination of adrenocortical function: urinary 17-ketosteroids,P urinary 17-hydroxycorticosteroids,a urinary pregnanetriol,’ plasma cortisoL6 RESULTS

Clinicalfeatures. Table 1 summarizes the clinical features of the five cases. The age at the time of diagnosis ranged from 8 mo to 11 yr. Four of the five patients were girls, coinciding with other published figures,l+s showing a predominance of females among the bearers of this disease, and paralleling the increased incidence in females of Cushing’s syndrome due to adrenal hyperplasia. Signs and symptoms had been present for from 2 mo to 18 mo prior to our initial evaluation. Virilization was the predominant feature in three children (Fig. 1A) and Cushing’s syndrome in two (Fig. 1B). In adults, Cushing’s syndrome is usually the result of adrenocortical hyperplasia, whereas in children, 60%80% of cases are From the Departments of Surgery and Oncology. Royal Manchester Children’s Hospital and Booth Hall Hospital, Manchester, England. Presented before the 20th International Congress of the British Association of Paediatric Surgeons, London, England, July 2%27,1973. David R. Stewart, M.D., Senior Registrar in Paediattie Surgery, Royal Manchester Children’s Hospital, Manchester. England. Patricia H. Morris Jones, M.R.C.P., Consultant Oncologtst, Royal Manchester Children’s Hospital, Manchester, England. Ambrose Jolleys, F.R.C.S., Consultant Paediatric Surgeon, Royal Manchester Children’s Hospital, Manchester, England. Address for reprint requests: David R. Stewart, M.D.. Primary Children’s Hospital, 320 Twelfth Avenue, Salt Lake City, Utah 84103. (D1974 by Grune & Stratton, Inc. Journal of Pediatric Surgery, Vol. 9, No. 1 (February). 1974

59

STEWART.

60

MORRIS

JONES,

AN0

JOLLEYS

Table 1. Clinical Features of Five Children with Functioning Adrenocortical Duratmn Age Patlent

IV)

SW

J.H.

9/12

F

Symptoms

Presenting

Physacal

MO)

Symptoms

Findmgs

4

Acne,

sweating.

pubic

flushing.

hair

BP 125/70, mass,

left abdominal

T clitoris.

pubic

hair, acne S.F.

18/12

F

9

Rapid

wt

tism. C.W.

8/12

F

2

A.B.

3

F

18

Hemangloma Rapid

wt

pubic H.H.

11

M

8

gain,

buffalo

Rapid

ti

gain,

acne.

hirsu-

It. arm T clitoris,

hair gain,

BP 130/80;

Cushingoid

Pubic

hair,

tt. abd.

Pubic

hair, 1 clitoris.

hump

Cushingoid. abd.

pam

Cushingoid.

mass

BP 1 1 O/80 BP 150185

caused by carcinoma.g*lo Virilization, on the other hand, may be produced by either hyperplasia or an adrenal tumor. One child with Cushing’s syndrome had signs of virilization as well, a presentation which is not uncommon in cases of adrenal carcinoma. The tumor often produces increased amounts of both glucocorticoids and androgens, and Heinbecker” found that adrenocortical carcinoma was less likely to produce a “pure” syndrome than was adrenal hyperplasia. We have had no “pure” feminizing tumors of the adrenal cortex, and, although several cases have been reported, (12-15) feminization is recognized as a very rare manifestation of adrenocortical carcinoma at any age. Facial acne, reflecting increased circulating plasma cortisol, was the first sign noted in two children and we feel that the presence of acne in an infant should be considered pathognomonic of an adrenocortical lesion, Another frequent sign is rapid increase in height and weight, usually in association with secondary sexual changes. Although an abdominal mass was readily palpable in two cases, this was not the presenting complaint, unlike most other childhood cancers in which the presence of

Fig. 1 (A) Three-year-old girl with marked virilizing changes, including deepening of her voice. (81 H.H.. agad 11 yr, showing the classical features of Cushings syndrome.

CARCINOMA

OF ADRENAL

GLAND

61

a mass is the first and frequently the only indication of a tumor. Hypertension, a nonspecific symptom noted by others,8*10~1ewas documented in four of our five cases. Two of the patients had a history of carcinoma in the family, and other9 have noted the high incidence of malignant tumors in the families and relatives of children with virilizing adrenal tumors. We have had no children with associated hemihypertrophy, urinary tract anomalies, or astrocytomas, although these have been reported” as concomitants of the disease. Ten per cent of the cases reported by Fraumeni and Miller” were found to have associated cutaneous lesions requiring treatment, and one of our patients presented with a hemangioma on her arm, whereupon she was noted to have virilizing changes and an abdominal mass. Although we have not encountered hypoglycemia in association with adrenal carcinoma, it is acknowledged to be an infrequent symptom of the disease. It may not be the result of the secretion of a particular type of steroid by the tumor but may have the same origin as the hypoglycemia accompanying other large retroperitoneal tumors.’ Diagnosis

Routine laboratory studies were normal in all. The glucose tolerance test merely served to verify the diagnosis of adrenal hyperactivity and was not specifically diagnostic of its cause. The urine 17 keto- and 17-hydroxycorticosteroids were elevated in all five of our cases (Table 2), and their excretion was unaffected by dexamethasone administration, suggesting the diagnosis of tumor rather than adrenocortical hyperplasia. The determination of urinary steroid excretion and its response to dexamethasone is the most useful means of distinguishing adrenocortical tumors from hyperplasia of the gland (Table 3). Characteristically, the 17ketosteroid excretion is markedly elevated in carcinoma, accompanied, often, by a less marked elevation in 17-hydroxycorticoid excretion. This is usually the case regardless of whether the dominant clinical feature is virilization or Cushing’s syndrome. Hyperplasia, on the other hand, frequently results in less elevated levels of urinary steroid excretion. The administration of 2 mg of dexamethasone every 6 hr for 48 hr has no effect on urinary steroid excretion in patients with carcinoma because the production of steroids by the tumor is not dependent upon ACTH stimulation. Adrenocortical hyperplasia responds to suppression of ACTH by exogenous steroids, resulting in a marked reduction in endogenous steroid production and a fall in urinary steroid excretion. Conversely, an infusion of ACTH causes a rise in urinary steroid production in patients with hyperplasia and has no effect on those with adrenocortical carcinoma. Adenomas are said’* to have an increase in 17-hydroxycorticoid excretion after ACTH infusion, although this appears to be a variable response. Another useful diagnostic consideration is the fact that the serum cortisol is elevated, without a diurnal variation, in cases of carcinoma, whereas diurnal variation may occur in patients with hyperplasia. In addition, the latter group has an elevated serum ACTH level, in contrast to the low level found in patients with carcinoma. Other diagnostic studies include the determination of the beta fraction of 17-ketosteroids, said to be increased in carcinoma,7~22and the measurement of tetrahydro substance (THS) in the urine. Lipsett et al.’ have shown that THS is the major component of the 17-hydroxycorticoids excreted in patients with carcinoma, whereas it occurs to only a limited extent in

STEWART,

62

Table 2. Operative Adrenocortical

Procedure and Postoperative

Carcinoma.

Note the Increased Indicating

Pl

SF

17-KS

50

Pregn

17.KS

AND JOLLEYS

Course of Five Children With Functioning

Recurrence

of the Tumor

Excretmn (mg/24

Decadron

17.KGS

JONES,

Excretion in Patient H.H. 6 Months After Operation,

Urinary Steroid Control

MORRIS

hr)

Postoperative 17.KGS

48

Other Postoperative

17-KS

DW

17.KGS

17.KS

17.KGS

36

4wk

14wk 6 mo 6 l/2 AS

17.3

13.0

13.0

10.0

0.6

mo

0.8

0.8

4.9

12.5

1913173

0.8

1.8

16.5

30.2

2wk

1 .o

Nil

22

22

14wk

1.5

5.0

20.5

14.5

14wk

0.5

3.0

22.5

14.0

0.6

3.6

18.5

10.0

9 l/2

mo

ACTH 1.5

16.5

Metapirone 0.4

0.15

0.7

0.6

0.2

0.3

0.3 0.7

-

0.8 0.7 1.2 ACTH 4.0 JH

33

7.0 60 postop

HH

cw

41

53 (62)

2wk

0.8

3mo

0.5

1 .o

5 mo

0.2

0.3

2.0

37.5

54.5

3wk

1 .o

7.5

44

56

6wk

1.5

10.0

41

65.5

4mo

2.0

5

40

59(61)

6mo

6.2

26

43

22

50

2wk

0.22

5mo

0.1

18mo

0.6

15

ACTH preop 48.5

75.5178)

0.9

patients with adrenocortical hyperplasia or adenoma. Finally, increased amounts of pregnanetriol in the urine of a virilized child reportedly’ signifies hyperplasia rather than tumor. The IVP showed a suprarenal mass in four of the five cases, supporting the diagnosis of a tumor. We employed angiography in two cases and we feel that it is a, valuable tool for the differentiation of hyperplasia from cancer. Nephrotomography has also been suggested for this purpose in the event that the IVP is normal. Pneumoretroperitoneum appears to have been replaced by more specific techniques in the diagnosis of adrenal lesions. Bone age, based on roentgenograms of the hand, may be advanced in patients with adrenal carcinoma, but taken by itself it represents only a sign of adrenal hyperactivity from any cause. Three of our tumors originated on the right side, a figure which compares with Kenny’s series8 in which four of seven tumors were right sided. Other authors, however,e~7*18~20 in large groups comprised primarily of adults, found a significant incidence of the tumor on the left side.

CARCINOMA

OF ADRENAL

Table 3.

GLAND

63

Diagnostic

Studies Commonly

Functioning Adrenocorticel Urnnary Steroids

Used in Distinguishing Lesions

Serum

ACTH

Decadron

ACTH

Cortisol

Lsvel

Suppression

Infusion

Comment

No response

Rapid onset of

T Carcinoma

No diurnal

17~sf 170~~~1

LOW

variation

No

symptoms;

response

usually mixed syndromes

T Adenoma

Normal or somewhat

No diurnal variation

Normal or low

Usually minimal

Marked 17 OHCS

T

-

response Hyperplasia

T

T

T

Reduction in urine

170HCSf

Generally pure syndromes

steroids

Initial Therapy

The tumor was surgically removed, using a transabdominal approach, in all five patients. Meticulous attention was paid to preoperative and intraoperative steroid management. We have generally used ~00-200 mg of cortisone acetate intramuscularly the night before operation, and a similar dose of hydrocortisone intravenously during the operation. In two cases the tumor was not felt to have been completely excised. One of these patients (H.H.) had metastatic disease in his liver at the time of initial operation, and he subsequently died despite the use of radiation therapy. In the second case (S.F.) the tumor was felt to extend up into the vena cava, although there was no evident involvement of the liver. The primary was excised, leaving the apparent venous extension, and this patient is alive and well 1 yr after operation and radiation therapy. In one case it was necessary to perform a nephrectomy in order to ensure complete removal of the tumor, but ipsilateral nephrectomy is not usually required. We have used the transabdominal approach rather than a retroperitoneal or posterior approach not only for better exposure but because we feel that this offers the best opportunity to evaluate the contralateral adrenal gland, as well as to assess the extent of metastatic disease within the abdomen. In most instances of functioning adrenocortical carcinoma, the contralateral adrenal gland is atrophic as a result of suppression by the high levels of circulating hormone produced by the tumor. Pathology

Four of the five cases were felt clearly to be carcinomas of the adrenal cortex. In one case, the histologic picture of the tumor was more benign, consistent with an adenoma. Although this child represents our longest survivor, 12 yr, it should be noted that the distinction between benign and malignant tumors of the adrenal cortex is often difficult, and neoplasia with a histologic appearance almost identical to normal adrenal tissue may recur and produce metastases.21 Furthermore, capsular invasion by the primary tumor has been reported in cases which were histologically benign. The appearance of adrenal carcinoma is often not unlike that of normal adrenal tissue grossly, although it usually is not encapsulated. The tumors are frequently

64

STEWART,

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AND JOLLEYS

Fig. 2 (Al Adrenocortical carcinoma with a histologic appearance not unlike that of normal zona glomerulosa. Hematoxylin and eosin. x 100. (B) Adrenocortical carcinoma with a disorderly array of undifferentiated and pleomorphic cells. Hematoxylin and eosin. x 100

tan or yellow in color and may have focal areas of necrosis, hemorrhage, or calcification. Microscopically, the tumor may closely resemble normal adrenal tissue (Fig. 2A) with a cord-like arrangement of cells of relatively normal size resembling the zona glomerulosa of normal adrenal cortex. There may be giant tumor cells and granular eosinophillic cells as well. The more undifferentiated tumors demonstrate a sarcomatous pattern (Fig. 2B) with marked pleomorphism and a disorderly array of cells. It is difficult to correlate endocrine function with histologic presentation, but Huvos et al.e felt that functioning tumors in general were characterized by enlarged eosinophilic cells with either a ribbonlike or trabecular growth pattern. Metastases, when they occur, are most frequently found in the lung, the liver, and the regional lymph nodes. Spread to bone and brain is highly unusua1.7~22Like other retroperitoneal tumors, adrenocortical carcinoma spreads locally and invades mesentery, omentum, and kidney, forming large intra-abdominal tumors that may erode viscera or invade the large abdominal veins. Postoperative Treatment and Course of the Disease (Table 4)

Postoperatively, all five children were maintained on steroids for several months, and we feel, as do others,1,22 that this is critical to the successful management of these notoriously fragile patients. The rather poor long-term survival of children

CARCINOMA OF ADRENAL GLAND

66

Table 4. Opamtiva Procedum and Postopamtive Coume of Five Childmn With Admnocortical Carcinoma Pt JH

Operative Findings Large It. adrenal tumor:

Pathologic Diagnosis

Other Treatment

Carcinoma

2600 R to abdomen

No recurrence at

Carcinoma

2500

R to abdomen

1 vr No recurrence at

Carcinoma

3000

R to abdomen

1 Yr No recurrence at

no metastasas SF

large r-t. adrenal tumor

Cw

Large rt. adrenal tumor;

Follow-up

extending into vana cava positive nodes in renal

9 vr

hilum A9

Rt. adrenal tumor; no

No recurrence at

Adenoma

metastaaae HH

Large It. adrenal tumor:

12 yr Carcinoma

1500 R to abdomen

Recurrence and

positive aortic nodes;

death 9 mo after

probable liver

operation

involvement

with adrenocortical carcinoma in part reflects inaccurate management of their steroid balance. In most cases the uninvolved adrenal, which has been suppressed by the functioning tumor, recovers its normal function, and it is possible to discontinue steroid therapy after several months. Even in these children, however, mild adrenal crises may be precipitated by periods of stress or illness. Adrenocortical function should be carefully monitored by the determination of 24-hr urinary steroid excretion at frequent intervals postoperatively. In one case (H.H.) a marked increase in these values was an accurate indication of the recurrence of the tumor after 6 mo. A few cases have been reported” of congenital absence of the other adrenal gland in children with adrenocortical carcinoma, and in these instances, steroid replacement will obviously need to be continued indefinitely. This situation should be recognized either at operation or by the lack of urinary steroid excretion as the exogenous steroids are reduced. Four of the five patients received radiation therapy postoperatively. This consisted of 2500 rads to the abdomen with shielding of the contralateral kidney and adrenal, There has been only one reported case of bilateral adrenocortical carcinoma,2a and prophylactic irradiation of the unaffected gland appears to have no place. Most authors reporting on groups of adult cases of adrenocortical carcinoma7*20~22 feel that adult adrenocortical carcinoma is radioresistant and have not recommended the use of radiation therapy for the disease. We have not employed chemotherapy in the treatment of this disease although some authorsz4 have suggested treatment with o, p-DDD. This drug has been shown to cause a marked decrease in the secretion rate of 17-hydroxycorticosteroids and to produce extensive destruction and fibrosis of adrenocortical cells. Several authorsa4*sa reported a significant regression of measurable metastatic lesions in patients with functioning adrenocortical carcinoma who were given ortho, para DDD and it may be that this drug has some place in the treatment of metastatic cancer of the adrenal cortex but its primary effect seems to be the amelioration of the endocrine symptoms produced by the functioning tumor without necessarily prolonging the useful life of the patient. At the present time four of our five patients are surviving, without evidence of

66

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AND JOLLEYS

recurrence, for from 1 to 12 yr after operation. The factors relating to survival in these cases are difficult to assess, but, based on our experience, we irradiate any child with an adrenocortical tumor, regardless of its histologic appearance. Support for this is derived from one of our cases (S.F.) in whom at the time of initial operation there was noted to be tumor invading the vena cava which could not be removed. She received a course of 2500 rads to the abdomen and at a subsequent reexploration there was no evidence of tumor within the abdomen. Unlike some other childhood tumors, adrenal carcinomas appear not to be prone to metastasize early, as evidenced by one of our patients (C.W.), now surviving 6 yr after operation, who had been noted to have virilizing changes for at least a year prior to being seen. At operation there were no metastases present and the tumor was relatively easily removed. Adult adrenocortical carcinoma, on the other hand, appears to be generally a highly malignant tumor leading to death soon after the onset of symptoms. In one series,’ 50% of the patients died within 2 yr of the onset of symptoms. SUMMARY

Five cases of functioning adrenocortical carcinoma in children aged 8 mo to 11 yr have been treated in Manchester since 1953. Their endocrine signs and symptoms were those of either Cushing’s syndrome or virilization or both. Differentiation of these patients from those with adrenocortical carcinoma was best accomplished by means of measurement of the 24-hr urinary steroid excretion and its response to dexamethazone infusion as well as by the use of an intravenous pyelogram and an angiogram. All children were treated by surgical removal of the tumor and postoperative irradiation with careful management of their steroid balance before, during, and after operation. Four of the five are living and free of recurrence for from 1 to 12 yr after operation. ACKNOWLEDGMENT We express our thanks to Miss E. M. Hammond, B.Sc., who performed all the biochemical determinations on these cases. REFERENCES I. Hayles AB, Hahn HB, Sprague RG, et al: _ 6. Huvos, AG, Hajdu SE, Brasfield RD, et al: Hormone-secreting tumors of the adrenal cortex Adrenal cortical carcinoma, clinicopathologic in children. Pediatrics 37:19, 1966 study of 34 cases. Cancer 25:354, 1970 7. Lipsett MB, Hertz R, Ross GT: Clinical and 2. Norymberski JK, Stubbs RD, West HF: pathologic aspects of adrenocortical carcinoma. The determination of 17 ketosteroids in the urine. Am J Med 35:374,1963 Lancet 1:1276, 1953 8. Kenny FM, Hashida Y, Askari HA, et al: 3. Few, JD: A method for the analysis of uriVirilizing tumors of the adrenal cortex. Am J Dis nary 17 hydroxycorticosteroids. J Endocrinol Child 115445, 1968 22:31, 1961 9. Gilbert MG, Cleveland WW: Cushing’s syn4. Bell M, Varley H: Estimation of pregnanetdrome in infancy. Pediatrics 46:217, 1970 riol and 17 hydroxypregnanolone in urine in con10. Tank ES, Bartlett JD, Herwig KR, et al: genital adrenal hyperplasia. Clin Chim Acta Surgery of the adrenal glands in infancy and 5396, 1960 childhood. J Ural 106:280, 1971 5. Mattingly D: A simple fluorimetric method I 1. Heinbecker P, O’Neal LW, Ackerman LV: for the estimation of free I1 hydroxycorticoids in Functioning and non functioning adrenal cortical human plasma. J Clin Pathol 15374, 1962 tumors. Surg Gynecol Obstet 105:21, 1957

CARCINOMA

OF ADRENAL

GLAND

12. Halmi KA, Lascari AD: Conversion of virilization to feminization in a young girl with adrenal cortical carcinoma. Cancer 27:931, 1971 13. Bacon GE, Lowrey GH: Feminizing adrenal tumor in a 6-yr-old boy. J Clin Endocrinol25: 1403, 1965 14. Gabrilove JL, Nicolis GL, Hausknecht RU, et al: Feminizing adrenocortical carcinoma in a man. Cancer 25: 153, 1970 15. Wallach S, Brown H, Englert E, et al: Adrenocortical carcinoma with gynecomastia. A case report and review of the literature. J Clin Endocrinol 17:945, 1957 16. Gross RE: Neoplasia producing endocrine disturbances in childhood. Am J Dis Child 59:579, 1940 17. Fraumeni JF, Miller RW: Adrenocortical neoplasms with hemihypertrophy, brain tumors and other disorders. J Pediatr 70:129, 1967 18. Scott HW, Foster JH, Rhamy RK, et al: Surgical management of adrenocortical tumors

67

with Cushing’s syndrome. Ann Surg 173:892, 1971 19. Rapaport E, Goldberg MB, Gordan GS, et al: Mortality in surgically treated adrenocortical tumors. Postgrad Med 2:325, 1952 20. MacFarlane DA: Cancer of the adrenal cortex. Ann Roy Co11Surg 23:155, 1958 21. Marsden HB, Steward JK: Tumors in children, in Recent Results in Cancer Research. Springer-Verlag, New York, 1968, pp 292-295 22. Hutter AM, Kayhoe DE: Adrenal cortical carcinoma. Clinical features of 138 patients. Am J Med41:572, 1966 23. Loridan L, Senior B: Cushing’s syndrome in infancy. J Pediatr 75:349, 1969 24. Hutter AM, Kayhoe DE: Adrenal cortical carcinoma. Results of treatment with 0, P’ DDD in 138 patients. Am J Med41:581, 1966 25. Bergenstal DM, Hertz R, Lipsett MB, et al: Chemotherapy of adrenocortical cancer with 0, P’ DDD. Ann Intern Med 53:672, 1960