Adrenocortical Carcinoma in Children: Clinical Aspects and Prognosis
By Cesar C. Sabbaga, Sylvio G. Avilla, Claudio Schulz, João C. Garbers, and Decio Blucher Curitiba, Brazil
. Although adrenocortical carcinoma is seen infrequently in children in most countries, it is occurs with significant frequency in Southern Brazil. This has enabled a study of the pattern of this disease in the pediatric age group. Of 78 patients with adrenocortical carcinoma seen at two hospitals in Curitiba, Brazil, 55 were adequately documented, with minimum of 2 years’ follow-up, and formed the basis of this paper. Ninety-five percent of the patients showed some degree of virilization, notably pubic and / or body hair, clitoris or penis enlargement, and adult voice. Cushing’s syndrome was present in 73% of these cases. The prognosis is age related and is dependent on the resectability of the tumor. Whereas 82% of the children under the age of 2 years survived, the figure for those over the age of 2 years was only 29%. When total resection of the tumor was possible, the survival rate was 67%, with no survival when only partial excision was performed.
Copyright @ 1993 by W.B. Saunders Company
INDEX WORDS: Adrenocortical carcinoma, pediatric.
A DRENOCORTICAL carcinoma (ACC) is a highly malignant tumor, rarely seen in most parts of the world. Its onset has two peaks of incidence: the first between 1 and 12 years of age (80% under 5 years), and the second between the 4th and 5th decade of life. Because of its low incidence, there are no established treatment protocols or uniform histo- logical classification. Factors that directly influence the prognosis and biological behavior are poorly understood. In Southern Brazil, ACC is seen with great frequency,’ and our experience has shown that this tumor has the same incidence as Wilms’ tumor, neuroblastoma, and non-Hodgkin’s lymphoma. The aim of this study is to establish the clinical features and the main prognostic factors of the tumor.
MATERIALS AND METHODS
A retrospective review of the admission records of 78 patients with ACC (1969 to 1991) at two hospitals in Curitiba, PR, Brazil, Hospital de Clinicas da Universidade Federal do Parana and Hospital Infantil Pequeno Principe, found 55 patients with a minimum 2-year follow-up. Factors studied included age, sex, race, clinical features, complementary examinations, interval between onset of the disease and diagnosis, instituted treatment, local recurrence, metastases, diameter and weight of the tumor, side of the tumor, operative rupture, presence of local invasion, and the relationship of these factors to the 2-year survival rate. Statistical analysis was performed with the Z test, with significance granted to P values < . 05.
RESULTS
The clinical features are summarized in Table 1. Clinical signs of virilization were commonly seen and
included pubic and/or body hair (95%), clitoris or penis enlargement (70%), and adult voice (50%). Seventy-four percent presented with Cushing’s syn- drome and most of these had significant arterial hypertension. In only two patients was the presenta- tion of a mass the only significant initial finding, and only one showed evidence of feminization. Forty-one (74%) were under the age of 5 years and 17 (31%) were under the age of 2 years. Fifty-one were Cauca- sian, and 42 (76%) were females. All patients had high levels of 17-ketosteroids and 44 (80%) had elevated urinary 17-hydrocorticoids. Plasma testoster- one and dehydroepiandrosterone were measured in 24 children and were found to be high in 18. Dexa- methasone suppression tests were performed in 12 children without any decrease in hormone levels.
A tumor was palpable in 31 children (67%), includ- ing two in whom it was the only clinical finding. In the 24 children without a palpable tumor, computed tomography or ultrasonography was positive, en- abling identification of the tumor. Excretory urogra- phy was performed and was found to be normal in 13. The tumor was right-sided in 31 (57%) and left-sided in 24 (43%); there were no bilateral tumors.
The overall survival rate for children with ACC in this series was 46%. In children under the age of 2 years, the survival was 83% (14/17), whereas in children over the age of 2 years the figure was 36% (11/38). The survival rate was also influenced by duration of symptoms. When symptoms had been present for less than 6 months, the survival was 70% (23/33), compared with 9% (2/22) when symptoms had been present for more than 6 months. Of the 37 patients on whom total excision was performed, 25 (67%) survived, but in 14 (38%) there was local recurrence. These 14 patients include 9 in whom the tumor was entirely restricted to the adrenal gland as noted at the original operation and 5 in whom tumor was locally invasive.
Address reprint requests to Dr Cesar C. Sabbaga, Hospital Infantil Pequeno Principe, Rua Desembargador Motta. 1070, Curitiba-PR- Brazil CEP 80250-060.
| Type | No. (%) |
|---|---|
| Virilization + Cushing's syndrome | 40 (72.8) |
| Virilization | 12 (21.8) |
| Asymptomatic | 2 (3.6) |
| Feminization | 1 (1.8) |
| Total | 55 (100) |
In 10 children metastatic disease was present at the time of diagnosis, and in another 20, metastases later appeared. All the patients with metastases had local recurrence and the distribution of metastases was as follows: liver (6), lung (5), bone (3), pancreas (3), and brain (2).
Sex of the patient, method of presentation, pres- ence of local invasion, laterality of the tumor, opera- tive rupture, diameter, and weight of the tumor did not appear to influence survival.
DISCUSSION
The presence of adult-type pubic hair in a child must suggest the possibility of an adrenocortical tumor. This clinical finding was present in 95% of the patients in our series, and often associated with other signs of virilization. Due to the high incidence of this tumor in our area, pediatricians have been more familiar with the clinical manifestations of it, particu- larly the virilizing features. This enables us to see these patients in the early stages of the disease, particularly during the most recent part of our survey.
The most important prognostic factors that we were able to identify include age, therapeutic regi- men, duration of symptoms before diagnosis, and postresection recurrence.
Age appears to be the most significant of these, as previously identified by Humphrey et al.2 In their series they recognized two groups. Children under the age of 7 years (75% under 2 years) had a survival rate of 53%, whereas children aged between 9 to 16 years had a survival rate of only 17%. We found the correlation to be statistically significant in relation to children younger or older than 2 years.
With reference to the extent of resection, we have found that the most important prognostic factor for long-term survival is total excision of the tumor. Of the 55 patients analyzed, total resection was possible in 37 with 25 (67%) surviving. In those patients who had only biopsy or subtotal resection, there were no survivors, despite the addition of chemotherapy and radiation therapy (Table 2).
Adjuvant chemotherapy has shown poor results. Ortho-para-DDD (o-p’-DDD) has been used since 1966. Hutter and Hayhoe3 were the first to report
positive results with this therapy, although these were not observed by Hutchinson and Hein,4 Holcombe et al,5 or Raney et al.6 Zaitoon and Mackie7 stated that the drug acts directly on the adrenal cortex by inducing a blockage of hormonal release by the tumor. This reduces the effects of the excessive hormone, such as hypertension, gastrointestinal dis- turbances and neuromuscular effects, but does not interfere with the evolution of the disease. We had poor results using the drug in 8 patients with metasta- ses. It was also ineffective in reducing tumor volume in 4 patients with large nonresectable tumors. Re- cently, drugs such as adriamycin, cyclophosphamide, vincristine, and cis-platin have been used, but due to the small number of patients, no conclusion can yet be drawn.
Radiotherapy (1,000 cGy) was used in 4 inoperable patients and was ineffective in reducing tumor mass.
Duration of symptoms was also significant and when symptoms were present for longer than 6 months, the survival rate fell dramatically. In the 33 patients who had symptoms for 6 months or longer, total resection was possible in 23, but only in a very small percentage of those who had symptoms for longer than 6 months.
Local recurrence was seen in 14 of 37 patients who underwent total excision, with survival of two. Local recurrence following a presumably adequate resec- tion often presaged metastatic disease. Local recur- rence was seen more frequently in children over the age of 2 years (58%) than under this age (15%).
Finally, we analyzed the significance of tumor size. In MacFarlane’s judgment,8 the volume of tumor mass was relevant to the prognosis. LeFevre et al9 found that in his treated cases, 94% of the tumors weighing under 150 g survived, in opposition to only 22% survival when the tumor weighed over 150 g. Hough et al10 stated that, considering morphological criteria, the tumor mass was the most significant factor in predicting the development of metastases. However, Holcombe et al5 reported that 5 of their 13 pediatric patients had large tumors with 3 survivors.
| Type of Treatment | Total | Survived | % |
|---|---|---|---|
| Total excision | 35 | 24 | (68) |
| Total excision + chemotherapy | 2 | 1 | |
| Partial excision | 4 | 0 | |
| Partial excision + chemotherapy | 3 | 0 | |
| Biopsy + chemotherapy | 5 | 0 | |
| Chemotherapy + radiation | 2 | 0 | |
| Radiation | 2 | 0 | |
| No treatment | 2 | 0 | |
| Total | 55 | 25 | (46) |
In the present series, we found no statistical signifi- cance when comparing the size of the tumor and survival.
In the present large series, age under 2 years, early
diagnosis (<6 months of symptoms) and complete resection were associated with good patient survival. This was accomplished by rapid evaluation of chil- dren presenting with the onset of virilizing symptoms.
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