Pediatric Articles
ADRENOCORTICAL CARCINOMA IN CHILDREN
ROBERT KAY, O. PETER SCHUMACHER AND EDWARD S. TANK
From the Division of Pediatric Urology, Department of Urology, Cleveland Clinic Foundation, Cleveland, Ohio, and Department of Urology, University of Oregon Health Sciences Center, Portland, Oregon
ABSTRACT
Adrenocortical carcinoma in childhood is a rare yet potentially fatal disease. We present 5 cases of adrenocortical carcinoma detected and managed in childhood. Of the 5 patients 4 presented with clinical signs of excess corticosteroid production and 1 presented suddenly with abdominal pain. All patients had palpable abdominal masses. All tumors were removed surgically and adjuvant therapy with mitotane was used in 4 children. Two patients are alive and 3 are dead. Our experience demonstrates that mitotane may be used safely in children, and that early diagnosis, aggressive surgical extirpation, and the use of mitotane and chemotherapy may lead to an increased survival of children with adrenocortical carcinoma.
Adrenocortical carcinoma in children comprises only 0.002 per cent of all childhood malignancies, thus, representing a rare yet potentially lethal disease.1 In contrast to adults, most adrenocortical tumors in childhood are hormonally functional and should be eligible for early detection, multimodal therapy and improved survival. In an effort to determine the effective- ness of treatment of adrenocortical carcinoma in children in contrast to treatment of the disease in adults we review our experience with this unusual tumor in 5 children.
MATERIALS AND METHODS
Five children with adrenocortical carcinoma were managed at the Cleveland Clinic Foundation and the University of Oregon Center for Health Sciences (table 1). Patient age at the time of diagnosis ranged from 11/2 to 16 years. Sex distribution included 3 girls and 2 boys.
As demonstrated in other series of children, 4 of the 5 patients presented with signs of increased steroid production, while only 1 presented with abdominal pain. All 5 had large abdominal masses at the time of presentation, yet none of the patients or their families was aware of this abnormality. The youngest child in the series presented with signs of Cushing’s syndrome and physical examination revealed left hemihyper- trophy as well as a large abdominal mass. Of the 5 patients 4 demonstrated increased steroid production as demonstrated by urinary 17-ketosteroids, ranging from 61 to 1,350 mg. per 24 hours (normal 4 to 17 mg./24 hours). Dexamethasone suppres- sion and other diagnostic studies were not performed since a delay in surgery was not believed to be warranted.
Excretory urography (IVP) was obtained in all patients. Four patients had a suprarenal mass and a displaced ipsilateral kidney. Of interest was the 16-year-old girl with a 4,000 gm. tumor who had a normal IVP but did demonstrate on comput- erized axial tomography a large retroperitoneal mass, suggest- ing its origin from the left adrenal.
Transabdominal surgical exploration was done on all patients and 2 patients required thoracoabdominal incisions (table 2). Two patients underwent adrenalectomy, while surgical excision in 3 included the ipsilateral kidney as part of the specimen. Of the 5 patients 3 were believed to have extensive disease, includ-
ing gross tumor venous thrombi in 2 and visible hepatic metas- tases in 1. The latter patient underwent partial hepatectomy 4 weeks after left nephroadrenalectomy.
Adjuvant therapy was used in 4 of the 5 patients. Mitotane was begun immediately in the postoperative period in 4 pa- tients, 3 of whom were believed to have extensive disease at surgery or remaining disease. One child was unable to take the medication secondary to gastrointestinal distress. Patient S. K., who was believed to have tumor thrombi incompletely resected, received mitotane for 2 years and 7 months, and is free of disease 12 years postoperatively. Vincristine, vinblastine and carmustine were used in the terminal phases of the pa- tients. Two patients are alive 12 and 20 years postoperatively. Three patients died at 2, 6, and 14 months postoperatively.
DISCUSSION
Adrenocortical carcinoma is an unusual tumor in childhood and represents a small percentage of tumors of the adrenal gland. In a review by Stewart and associates only 6 per cent of adrenal cancers in children were derived from the adrenal cortex.2 Neuroblastoma is certainly the most common carci- noma, representing >90 per cent of all adrenal cancers.
The natural history of adrenal carcinoma was noted by McFarlane when he showed that the mean survival of non- treated tumors was 2.5 months.3 In adults the tumor is a highly aggressive lethal disease with a mortality rate approaching 90 per cent.4 The exact survival figures in children are difficult to establish. In a review by Hayles and associates in 1966 only 23
| Pt .- Age-Sex (yrs.) | 17-Ketosteroids (4 to 17 mg./24 hrs.) | Presentation |
|---|---|---|
| SI-11/2-F | Increased × 3 | Hemihypertrophy, Cushing's syndrome, clitoromegaly |
| RB-21/2-M | 61 | Enlarged phallus, pubic hair, hypertension |
| SK-31/2-M | 1,350 | Enlarged phallus |
| DM-6-F | Normal | Abdominal pain and mass |
| KS-16-F | 1,013 | Acne, facial hair, clito- romegaly |
Accepted for publication May 20, 1983.
| Pt. | Operative Findings | Surgery | Adjuvant Therapy | Status |
|---|---|---|---|---|
| SI | Lt. adrenal tumor, 7 ×5×3cm. | Adrenalectomy | No | Alive, 20 yrs. |
| RB | Rt. adrenal tumor, 10×12 cm. (350 gm.) | Adrenalectomy | Mitotane and vinblastine | Dead, 14 mos. |
| SK | Rt. adrenal tumor (805 gm.), gross venous tumor em- boli invading liver capsule | Nephroadrenalectomy | Mitotane | Alive, 12 yrs. |
| DM KS | Rt. adrenal tumor, 10 × 5 cm., gross venous tumor emboli Lt. adrenal tumor, 21 × 18 cm. (4,000 gm.), liver metas- tases | Nephroadrenalectomy Nephroadrenalectomy, partial hepatectomy | Mitotane Mitotane | Dead, 2 mos. Dead, 6 mos. |
of 222 children survived with a hormone-secreting tumor of the adrenal cortex.5 Stewart and associates reported that 4 of 5 patients with adrenocortical carcinoma were free of disease, although followup was short and cannot be considered final.2 Our mortality of 3 of 5 patients (60 per cent) is discouraging and warrants closer inspection.
Adrenocortical carcinoma in children is unique in that its hormonal production leads to signs and symptoms that are alarming to the patients and physicians. It is interesting that all 5 of our patients had large abdominal masses, yet 4 sought medical attention for other physical changes relating to the excess steroid production. It is imperative that physicians rec- ognize Cushing’s syndrome and virilization as possible mani- festations of this potentially lethal disease. There have been 2 cases of Cushing’s syndrome reported with the late develop- ment of an adrenocortical carcinoma, 3 and 36 years after treatment of presumed adrenocortical hyperplasia.6,7 One can only hope that increased familiarity by physicians with this entity will lead to early detection and treatment.
It is well established that surgery is the mainstay of current treatment of this disease.4 Of our patients 3 underwent surgical resection in the face of either metastasis or extensive disease with venous tumor extension. Patient K. S. underwent partial hepatectomy in an effort to be free of disease. Patient S. K. with extensive disease is still alive with the use of surgery and adjuvant therapy, which we believe justifies the aggressive surgical approach to this problem in childhood.8
The exact role of adjuvant therapy in this disease has not been well established. Mitotane has been used extensively in adults with adrenocortical carcinoma but its effect in childhood is not well known. It was recognized in 1949 by Nelson and Woodard that the insecticide chlorophenothane (DDT) led to selective adrenal necrosis in dogs.9 In 1960 Bergenstal and associates demonstrated the use of the isomer of chloropheno- thane, mitotane, and the regression of metastatic adrenocorti- cal carcinoma.1º In 1973 Lubitz and associates demonstrated some improvement in survival with the use of mitotane but no patients were cured.11
We used mitotane in 4 of the 5 patients, including 2 who died within 2 and 6 months postoperatively and had extensive disease at the time of surgery. One patient previously reported on had extensive disease that was not believed to be completely resected at the time of surgery.8 He is free of disease 12 years after the original operation.
Mitotane has significant toxicity. In a review of the literature by Hutter and Kayhor only 11 per cent of the patients had no toxicity, while gastrointestinal distress was seen in 83 per cent, neurotoxocity in 41 per cent and skin rash in 14 per cent.12 Only 1 child in our series was unable to take the medication secondary to gastrointestinal distress. No other serious side effects were noted in our series. One child continues to require exogenous steroids 2 years after the discontinuation of mito- tane. He is free of disease 12 years after surgery and incomplete excision of the tumor.
Other adjuvant chemotherapeutic agents have been used in our series. Vincristine, vinblastine and carmustine were used in the terminal stages of the disease and were not effective. Other drugs reported in the literature, including cyclophospha- mide, actinomycin, 5-fluorouracil and doxorubicin, have been used but usually with poor results. There has been 1 report of a metastatic adrenal carcinoma cured by combination chemo- therapy with 5-fluorouracil and mitotane.13 Recently, cisplat- inum has been reported in the treatment of metastatic adren- ocortical carcinoma.14 This drug demonstrated substantial sub- jective and objective responses in 4 patients. However, all patients eventually died of the disease, with a mean survival of 17 months compared to 10 months with mitotane alone.
The role of radiotherapy has not been well established in childhood. It is recognized that adrenocortical carcinoma is radioresistant in adults and, generally, is not regarded as an effective form of treatment of this disease. In contrast, Stewart and associates administered 2,500 rad to 4 children with adren- ocortical carcinoma.2 Three patients with metastatic disease were treated with irradiation and no chemotherapy, and 2 survived. We did not use radiotherapy in our series and its use still remains in doubt.
Fraumeni and Miller demonstrated an association of adren- ocortical carcinoma with hemihypertrophy and other disor- ders.15 Patient S. I. is interesting in that she had hemihypertro- phy, and adrenocortical carcinoma developed early in life. It is postulated that these patients have a genetic predisposition to the neoplasm and must be followed carefully.16 Furthermore, Levine demonstrated the late development of other tumors in these unusual patients who have been cured previously of adrenocortical carcinoma.17 A review of the literature by Levine detected 6 patients with adrenocortical carcinoma and second- ary tumors, 4 of which were of central nervous system origin. Recently, Andler and associates reported a case of renal cell carcinoma following irradiation to the bed of a previously resected adrenocortical carcinoma.18 Patients with adrenocor- tical carcinoma must be under surveillance, especially if asso- ciated with other abnormalities such as hemihypertrophy, since they indeed may have a genetic predisposition to other neo- plasms.
REFERENCES
1. Young, J. L., Jr. and Miller, R. W .: Incidence of malignant tumors in U.S. children. J. Ped., 86: 254, 1975.
2. Stewart, D. R., Jones, P. H. and Jolleys, A .: Carcinoma of the adrenal gland in children. J. Ped. Surg., 9: 59, 1974.
3. MacFarlane, D. A .: Cancer of the adrenal cortex. The natural history, prognosis and treatment in a study of fifty-five cases. Ann. Roy. Coll. Surg. Engl., 23: 155, 1958.
4. Sullivan, M., Boileau, M. and Hodges, C. V .: Adrenal cortical carcinoma. J. Urol., 120: 660, 1978.
5. Hayles, A. B., Hahn, H. B., Jr., Sprague, R. G., Bahn, R. C. and Priestley, J. T .: Hormone-secreting tumors of the adrenal cortex in children. Pediatrics, 37: 19, 1966.
6. Korth-Schutz, S., Levine, L. S., Roth, J. A., Saenger, P. and New,
M. I .: Virilizing adrenal tumor in a child suppressed with dexa- methasone for three years. Effect of o,p-DDD on serum and urinary androgens. J. Clin. Endocr. Metab., 44: 433, 1977.
7. Nogeire, C., Fukushima, D. K., Hellman, L. and Boyar, R. M .: Virilizing adrenal cortical carcinoma. Cancer, 40: 307, 1977.
8. Becker, D. and Schumacher, O. P .: o,p’DDD therapy in invasive adrenocortical carcinoma. Ann. Intern. Med., 82: 677, 1975.
9. Nelson, A. A. and Woodard, G .: Severe adrenal cortical atrophy (cytotoxic) and hepatic damage produced in dogs by feeding 2,2- bis(parachlorophenyl)-1,1-dichloroethane (DDD or TDE). Arch. Path., 48: 387, 1949.
10. Bergenstal, D. M., Hertz, R., Lipsett, M. B. and Moy, R. H .: Chemotherapy of adrenocortical cancer with o,p’DDD. Ann. Intern. Med., 53: 672, 1960.
11. Lubitz, J. A., Freeman, L. and Okun, R .: Mitotane use in inoperable adrenal cortical carcinoma. J.A.M.A., 223: 1109, 1973.
12. Hutter, A. M., Jr. and Kayhor, D. E .: Adrenal cortical carcinoma. Results of treatment with o, pDDD in 138 patients. Amer. J. Med., 41: 581, 1966.
13. Ostuni, J. A. and Roginsky, M. S .: Metastatic adrenal cortical carcinoma. Documented cure with combined chemotherapy. Arch. Intern. Med., 135: 1257, 1975.
14. Tattersall, M. H., Lander, H., Bain, B., Stocks, A. E., Woods, R. L., Fox, R. M., Byrne, E., Trotten, J. R. and Roos, I .: Cis- platinum treatment of metastatic adrenal carcinoma. Med. J. Aust., 1: 419, 1980.
15. Fraumeni, J. F., Jr. and Miller, R. W .: Adrenocortical neoplasms with hemihypertrophy, brain tumor, and other disorders. J. Ped., 70: 129, 1967.
16. Tank, E. S. and Kay R .: Neoplasms associated with hemihypertro- phy, Beckwith-Wiedemann syndrome and aniridia. J. Urol., 124: 266, 1980.
17. Levine, G. W .: Adrenocortical carcinoma in two children with subsequent primary tumors. Amer. J. Dis. Child., 132: 238, 1978.
18. Andler, W., Havers, W., Stambolis, C., Medrano, J. and Stollmann, B .: Renal cell carcinoma following radiation therapy for an adrenal cortical carcinoma. J. Ped., 93: 634, 1978.