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Journal of Clinical Oncology, Vol 22, No 5 (March 1), 2004: pp. 838-845 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.08.085 Clinical and Outcome Characteristics of Children With Adrenocortical Tumors: A Report From the International Pediatric Adrenocortical Tumor RegistryFrom the Oncologic Pediatric Surgery Division, Erasto Gaertner Hospital, Liga Paranaense de Combate ao CÂncer, Curitiba; Division of Pediatric Endocrinology and Center for Molecular Genetics and Childhood Cancer Research (CEGEMPAC), Hospital de Clinicas, Federal University of Paraná, Curitiba, Paraná; the Biostatistics Division, Hemocentro, and The Instituto Domingos Boldrini, Universidade Estadual de Campinas, Campinas; Department of Pediatric Oncology, Universidade Federal de São Paulo, Escola Paulista de Medicina; Department of Pediatrics, São Paulo University Medical School, Sao Paulo, Brazil; the Departments of Pathology, the Department of Hematology-Oncology, and the International Outreach Program, St Jude Children's Research Hospital; and the Department of Pediatrics, University of Tennessee College of Medicine, Memphis, TN. Address reprint requests to Raul C. Ribeiro, MD, Department of Hematology-Oncology, St Jude Children's Research Hospital, 332 N Lauderdale St, Memphis, TN 38105-2794; e-mail: raul.ribeiro{at}stjude.org
PURPOSE: We created a registry for pediatric adrenocortical tumors (ACTs), which are rare and are not well characterized. We provide a descriptive analysis of 254 patients registered on the International Pediatric Adrenocortical Tumor Registry. PATIENTS AND METHODS: Between January 1990 and December 2001, 254 patients younger than 20 years of age with newly diagnosed or previously treated ACTs were registered. A histologic diagnosis of ACT was required, although central review was not mandatory. Follow-up information was periodically requested from the referring physician. Treatment was chosen by the primary physician. RESULTS: The overall female-male ratio was 1.6:1, but it varied widely among age groups. The most common presenting sign (84.2%) was virilization. Cushing's syndrome without virilization was uncommon (5.5%). Tumors were completely resected in 83% of patients. Patients with disseminated or residual disease received mitotane, cisplatin, etoposide, and/or doxorubicin, and rarely, radiation therapy. At a median follow-up of 2 years and 5 months, 157 patients (61.8%) survived without evidence of disease and 97 patients (38.2%) had died. The 5-year event-free survival estimate was 54.2% (95% CI, 48.2% to 60.2%). In a multivariate analysis, disease stage, presenting signs of endocrine dysfunction, and age were independently associated with prognosis. CONCLUSION: Childhood ACTs occur predominantly in females and almost always causes clinical signs. Complete resection is required for cure. Residual or metastatic disease carries a poor prognosis. Our results demonstrate the feasibility of a disease-specific database for obtaining meaningful clinical and outcome information.
Adrenocortical tumors (ACTs) are rare in children and adolescents. The Surveillance Epidemiology End Results data indicate about 14 new patient cases per year in individuals younger than age 20 years in the United States; ACTs represent 1.3% of all carcinomas in this age group [1]. Because of the rarity of pediatric ACTs, no single pediatric oncology center has acquired extensive experience with this tumor. Most reported series describe only a few patients observed over a period of several years [2]. Lefevre et al [3] analyzed the clinical characteristics and treatment outcomes of 42 children treated in several French hospitals over a 22-year period. They found a median age of 3.9 years, a predominance of girls, presenting signs of virilization in more than 90% of patients, and long-term survival of approximately 50%. Tumor size was the most important prognostic factor. The prevalence of increased predisposition to cancer (Li-Fraumeni syndrome) or other associated constitutional genetic syndromes was not reported. Similar clinical characteristics, treatment outcomes, and prognostic factors were observed among children with ACTs treated at a single institution in southern Brazil [4,5]. In a subsequent study, the Brazilian investigators found that the majority of these patients carried a germline p53 mutation [6]. In another study, Liou and Kay [7] summarized the clinical and outcome data of 412 patients from several published series, mostly from the United States. Again, the findings did not differ substantially from those previously described, suggesting that despite disparate geographic, ethnic, and genetic differences among patients, childhood ACTs seem to have a consistent clinical and biologic course [2]. To better define the clinical manifestations, prognostic factors, treatment, and outcome of childhood ACTs, we created a disease-specific database. Here we report the findings derived from 254 registered patient cases.
Eligibility Criteria and Data Collection Patients younger than 20 years with newly diagnosed or previously treated ACTs were registered and included in the study. All patient cases were reported by the patient's primary physician. Patients and their families were never contacted directly. All information was entered into a customized electronic database administered by a data manager. Data were reviewed by an International Pediatric Adrenocortical Tumor Registry (IPACTR) physician for consistency before entry. The referring physician was contacted directly if clarification was necessary. Central review of tumor histology was offered to the referring physician but was not a requirement for registration. Over the study period, the histology of approximately 80% of the patient cases was reviewed at St Jude Children's Research Hospital (Memphis, TN). Because of the difficulty of consistently discriminating adenomas from carcinomas in pediatric ACTs, patients with a diagnosis of either adenoma or carcinoma were included in the database. There was no central review of imaging studies, but all patients had imaging evaluation of the chest and abdomen and underwent extensive endocrine studies after surgery. Informed consent was obtained from all patients by the participating physicians. The extent of disease was retrospectively defined as localized or advanced on the basis of a modified staging system proposed previously (Table 1) [5,8]. Assignment to the localized disease (stage I or II) category required complete tumor resection and no evidence of disease elsewhere. Assignment to the advanced disease (stage III or IV) category required the presence of local residual or metastatic disease. When tumor weight was not provided, it was estimated from tumor measurements obtained from computed tomography scans, ultrasound examinations, or pathology reports by using the following formula: weight = 1.342 · (volume)0.8563 (Fig 1). In 30 patients, the tumor weight could not be determined because tumor volume was not available. Twelve of these 30 patients had distant tumor metastasis (stage IV), seven patients had local residual tumor (stage III), and the remaining 11 patients were classified arbitrarily on the basis of the largest tumor diameter measured by computed tomography or ultrasound examinations, or data reported by the pathologist. Tumors for which the largest diameter was less than 6 cm were classified as stage I disease.
On the basis of clinical data, tumors were classified as functional (causing virilization, Cushing's syndrome, Conn's syndrome, feminization, or mixed effects) or nonfunctional (no clinical signs of hormone excess). Information on tumor spillage during surgery and the presence of intravenous tumor thrombus was retrospectively obtained for the subset of patients treated in Curitiba, Brazil, directly from the patients' medical records.
Treatment
Statistical Analysis Survival curves were created using Kaplan-Meier [9] product limit estimates, and groups were compared using the log-rank test. The duration of overall survival was measured from the date of diagnosis to the date of death as a result of any cause. The duration of event-free survival (EFS) was measured from the date of complete response to the date of either local or distant relapse or death as a result of any cause. Complete response was defined as absence of any evidence of disease, either after initial surgery (patients with stage I and II disease) or after chemotherapy and/or definitive surgery (patients with stage III or IV disease). Failure to enter remission was considered an event at zero time. Patients who were lost to follow-up and had active disease at the last visit were considered to have had an adverse event at the time of the last visit. Data from all other patients were censored at the date of the last follow-up. Cox regression analyses and hazard function for the risk of death and relapse were used to identify factors associated with EFS rates in patients with limited disease (disease stage I or II); the forward stepwise method (Wald) was used to analyze the relation of survival to the following variables present at diagnosis: age, sex, presence of a clinical endocrine syndrome, interval between symptom onset and diagnosis, blood pressure, disease extent (stage I or II), complete tumor resection, tumor weight, tumor spillage, and presence of intravascular thrombosis. The level of statistical significance was prospectively determined to be P < .05. All analyses were performed by using SPSS software, version 10.1 (SPSS Inc, Chicago, IL).
Between January 1990 and December 2001, 259 patients were registered in the IPACTR. Five patients were excluded: four because a copy of the pathology report could not be obtained and one because of an incorrect diagnosis. Data on the remaining 254 patients were analyzed. Most of the patients (79.5%) were from southern Brazil. Thirteen percent were from the United States, and 7.5% were from nine other countries. Two-hundred twenty-eight tumors were histologically classified as carcinoma, and the remaining 26 were classified as adenoma. The median interval between the first symptoms and diagnosis was 5 months (range, 0 to 90 months).
The median age of the 156 girls and 98 boys was 3.2 years (range, 0 to 19 years). Approximately 60% of patients were younger than 4 years of age, and only 14% were older than 13 years of age. One child had a diagnosis of ACT during the neonatal period; another 18 patients had a history compatible with onset of overproduction of adrenal hormones during the first few months of life. The overall female-male ratio was 1.6:1, but it varied widely across age groups. Girls predominated in the age groups 0 to 3 years (ratio, 1.7:1) and
Approximately 90% of the children had clinical evidence of an endocrine syndrome. Virilization, alone or in combination with signs of overproduction of other adrenal hormones, was the most common clinical presentation (84.3%). Isolated Cushing's syndrome was rare. Tumors that did not cause clinical manifestations of hormone excess (nonfunctional tumors) were observed in 10.2% of patients. Isolated Cushing's syndrome (median age, 12.6 years) and nonfunctional tumors (median age, 5.7 years) tended to occur in the older children (P < .001; data not shown), without sex differences. Twelve patients were registered as having increased secretion of aldosterone, either alone (Conn's syndrome; n = 2) or together with oversecretion of other adrenocortical hormones (n = 10). The latter 10 patients had increased levels of androgens, glucocorticoids, and/or mineralocorticoids and were included in the mixed subgroup for analysis, although not all patients received a comprehensive laboratory hormone profile (Table 2). About two thirds of the patients had limited disease: 112 patients (44.1%) had stage I disease and 80 patients (31.5%) had stage II disease. Among patients with advanced disease, 25 patients (9.8%) had stage III and 37 patients (14.6%) had stage IV disease. Sites of metastasis were noted in 34 of these 37 patients. Eighteen patients had pulmonary metastasis, 11 patients had hepatic metastasis, and five patients had involvement of both liver and lungs. Tumor spillage during surgery was reported in 18 of 86 patients (21%) with stage I or II disease for which this information was available, whereas IV tumor thrombus was found in nine of 64 such patients (14%). In addition to surgery, seven of 116 patients with stage I disease received adjuvant treatment (five patients, mitotane; one patient, local radiotherapy; and one patient, combination chemotherapy). Of 80 patients with stage II disease, 16 received adjuvant treatment (13 patients, mitotane; two patients, combination chemotherapy; and one patient, local radiation). All patients with stage III or IV disease were treated with intensive chemotherapy. At a median follow-up of 2 years and 5 months (range, 5 days to 22 years), 157 patients (61.8%) remained alive and 97 patients (38.2%) had died. Death was associated with disease progression in 92 of these patients (including 22 patients who had active disease at the time of the last follow-up visit). Five patients died as a result of causes unrelated to tumor progression (two died as a result of infection, one died as a result of hypertensive complication, one died as a result of massive hemorrhage during surgery, and one died as a result of an unspecified complication). The 5-year EFS and overall survival estimates were 54.2% (95% CI, 48.2% to 60.2%) and 54.7% (95% CI, 48.7% to 60.7%), respectively (Fig 2).
Several clinical features, including age (Fig 3), sex, clinical syndrome, interval between first symptoms and diagnosis, blood pressure, disease stage (Fig 4), tumor spillage during surgery, IV tumor thrombus, and tumor weight were examined for association with outcome. Because consistent histologic criteria were not used to classify pediatric adrenocortical tumors as benign (adenoma) or malignant (carcinoma), these data were not examined as prognostic factors. However, among 26 patients reported to have adrenocortical adenoma, only one has experienced relapse.
In patients with localized disease, age between 0 and 3 years, virilization alone, normal blood pressure, disease stage I, absence of spillage during surgery, and tumor weight  200 g were associated with a greater probability of EFS (Table 3). In a Cox regression model analysis, only disease stage I, virilization alone, and age 0 to 3 years were independently associated with a greater probability of EFS (Table 4). When patients with adenoma were excluded, the overall results of the Cox regression analysis did not change (data not shown).
Because of the small number and dismal outcome of patients with stage III or IV disease, prognostic factor analysis was not performed in this group.
Our analysis of the IPACTR data suggests that pediatric ACTs are heterogeneous. Patients who have a diagnosis within the first 3 years of life tend to be girls, whereas an equal sex distribution is noted in the age interval 4 to 12 years. In adolescents, as in young children, there is a predominance of females. This age-dependent sex distribution is also seen in the Surveillance Epidemiology End Results data [1]. Girls and boys in the 0- to 3-year and 4- to 12-year age groups did not differ in presenting clinical and laboratory features or in constitutional p53 mutations [6], a finding that suggests that ACT in these two groups is the same disease but manifests itself earlier in girls than in boys. However, the clinical presentation seen in the older group differed from that observed in the younger groups. Adolescents and young adults tended to have Cushing's syndrome or nonfunctional tumors at presentation, whereas more than 90% of young children had virilizing features. Moreover, constitutional mutations of the p53 gene are frequently reported in young children with a diagnosis of ACTs [10,11], but are relatively rare in adults [12,13]. These observations suggest that pediatric ACTs comprise at least two subtypes. In the young child, the early manifestations of the disease, the predominance of virilizing tumors, and the tumor's histopathologic features [14] suggest that ACTs arise from the fetal zone of the fetal adrenal cortex. The fetal zone represents 85% of the adrenal cortex during fetal development and is oriented toward dehydroepiandrosterone production, as indicated by the fact that the fetal zone cells primarily express the enzyme 17a-hydroxylase/17,20 lyase (P450C17) [15]. In contrast, ACTs of adolescence and adulthood may originate from the definitive adrenal cortex. It is plausible that the presence of a constitutional p53 mutation increases the penetrance of ACTs in the fetal adrenal cortex but not in the definitive adrenal cortex. This premise is consistent with the fact that in individuals with constitutional p53 mutations (Li-Fraumeni syndrome), ACTs usually occur only during the first decade of life [16]. Because of the strong association between constitutional p53 mutations and a diagnosis of ACTs at a young age, genetic testing of these patients for p53 status should be considered. To date, no comparison of gene expression in pediatric and adult adrenocortical tumors has been reported. The reason(s) for the predominance of female sex in children with ACTs is not known. Approximately 12% of the patient cases with ACTs were diagnosed during the first year of life. One patient was diagnosed during the neonatal period. The clinical characteristics and outcome of the infants were similar to those of children aged 1 to 3 years at the time of diagnosis. There is a paucity of data on ACTs in the first few months of life. Satge et al [17] described one patient and reviewed the literature from 1900 to 1987. He found reports of 13 children with ACTs diagnosed during the neonatal period among 56 reviewed cases of solid malignancies. Eight patients reported before 1980 died as a result of postsurgical complications. Three neonates received no treatment and died during the first few days of life. Three patients, including the one reported by Satge et al [17], survived surgery but experienced relapse. Two died and one was free of disease 14 years after diagnosis. The latter patient was treated with mitotane at the time of relapse. Other sporadic cases of neonatal ACTs have been reported [18-23]. Interestingly, Saracco et al [18] reported the case of a newborn with ACT who had complete spontaneous resolution of tumor, including all metastatic lesions, 4 months after initial resection of the primary tumor. Most patients enrolled onto the registry were from southern Brazil. This fact reflects the increased incidence of the disease in this area (15 times greater than that in other geographic regions) and the heightened interest of investigators in this region. A unique constitutional p53 mutation was recently identified in the Brazilian patients [6,24], although the reason for the frequency of this abnormality in southern Brazil remains unclear. Patients reported from other countries rarely have been tested for constitutional or somatic p53 abnormalities. At St Jude, among 11 patients with ACTs who were tested, five had a constitutional p53 mutation (unpublished observation), although none had the specific mutation that was identified in the Brazilian patients. These registry data confirmed reports [2,4,7] that the diagnosis of ACTs is usually delayed. The median interval between the first signs or symptoms of ACTs and the diagnosis was 5 months (range, a few days to 8 years). The reasons for the delay are probably multifactorial. First, because small tumors can produce striking clinical manifestations, an extensive endocrine work-up may be required before the tumor is detected. Second, these children do not seem to be ill, except for their endocrine manifestations, and in fact, many experience accelerated growth and development. Finally, tumor growth can be slow, as shown by the time lag between parents' reported initial awareness of the clinical endocrine changes and detection of the tumor. This latter observation is consistent with a multistep process of carcinogenesis resulting from accumulation of genetic changes [25]. It can be argued that retrospective parental accounts are not reliable, but in some cases, these accounts were confirmed by photographs of the patients showing signs of overproduction of adrenal cortical hormones several years before diagnosis. Moreover, in a few cases, patients whose clinical and laboratory evaluation was consistent with increased production of adrenocortical hormones were lost to follow-up and then returned several years later, when the tumor was finally detected. Tumor classification based solely on the predominant clinical signs and symptoms (virilization and/or Cushing's syndrome) does not accurately reflect the tumor's hormonal secretory profile. For example, patients were rarely tested for aldosterone, renin, and estrogen levels. Therefore, many patients who were classified as having virilizing tumors might have been classified as having a mixed clinical and hormonal presentation if an extensive panel of adrenal hormones had been assayed. Hypertension was observed at the time of diagnosis in 43% of patients and was distributed among all clinical syndromes. In a few patients, it was severe enough to cause encephalopathy, which resulted in the death of one patient. Hypertension in these patients is attributed in part to tumor production of either glucocorticoids (in most patients) and/or mineralocorticoids. In fact, hypertension was significantly (P < .04) more common in patients presenting with Cushing's syndrome features than in other patients. However, 27% of patients with virilizing or nonfunctional tumors also had hypertension. In the latter patients, tumor compression of the renal artery or increased production of aldosterone may have contributed to hypertension. Regardless of the mechanism, hypertension resolved after tumor resection. Tumor size was useful in identifying patients at high risk of relapse after complete tumor resection. These data are consistent with the results of several studies [4,14,26-30] that found tumor size to be associated with prognosis. We estimated tumor weight, where it was not available, from tumor dimensions by using an equation derived from patients in this cohort for which both tumor weight and tumor dimensions were available. This equation was applicable specifically to our patient group, and it should not be used in other settings. As in many other pediatric malignancies, tumor burden is only a surrogate marker of more fundamental cellular events. Genetic studies of pediatric ACTs have disclosed several abnormalities, but their relation to prognosis is still unknown [31,32]. Interestingly, the interval between the first signs and symptoms and diagnosis was not associated with prognosis or tumor weight (data not shown); therefore, tumor size may reflect the quality of cumulative acquired genetic abnormalities. Thus, it seems that there is an initial phase of slow tumor progression characterized mainly by the endocrine manifestations in the absence of a palpable mass, and subsequent faster tumor progression. The types of still-unknown acquired genetic abnormalities are likely to determine the tumor's proliferative potential. This premise is consistent with observations that regardless of the interval between the first signs and symptoms and initial diagnosis, tumor growth and metastatic spread tend to occur rapidly in recurrent pediatric ACTs. Age younger than 4 years was independently associated with a better prognosis in a multivariate analysis. Other investigators also have reported better survival rates in young children than in older age groups [27]. Similarly, virilization as the sole clinical manifestation was associated with better prognosis. Patients with Cushing's syndrome as either the sole clinical manifestation or combined with other endocrine clinical syndromes (mixed), as well as those with nonfunctional tumors, had worse prognosis. However, these observations remain to be confirmed, given that many patients did not have an extensive laboratory evaluation for elevated levels of adrenal cortical hormones.
Disease staging criteria for childhood ACTs generally have not been agreed on. Most investigators use a classification scheme proposed by MacFarlane [33] and modified by Sullivan et al [34]. This classification, which is based on tumor size, lymph node involvement, and metastatic disease, was developed primarily for adults. In our study, we used a modification of the disease staging system proposed by Sandrini et al [5,8] These modifications were based on the premise that complete tumor resection and tumor size are the most important factors for disease control. These criteria allowed the identification of three distinctive prognostic groups. Patients with completely resected small tumors ( In summary, this analysis of the registry data confirmed that pediatric ACTs are more common in girls and are almost always associated with increased production of adrenal androgens. It also revealed that pediatric ACTs are heterogeneous and comprise at least two subtypes with different pathogenetic mechanisms. Regardless of the type, complete resection is mandatory for definitive disease control. Among patients who have had complete resection, tumor size is a strong prognostic indicator. In addition, this study demonstrates the feasibility of organizing a disease-specific database as a means of obtaining meaningful clinical and outcome information about rare pediatric malignancies.
The following referring physicians contributed to this study: M.R. Abboud, Lebanon; M. Abromowitch, USA; J.Y. Barbosa, USA; M. Bernstein, Canada; M.A. Champagne, Canada; J.C. Cordoba, Brazil; A.G. Cunha, Brazil; S.H. Diamond, USA; J. Falletta, USA; R.M. Ferreira, Brazil; A.S. Freiberg, USA; W. Furman, USA; D.J. Gnarra, USA; A.A. Green, USA; J. Greenberg, USA; F. Hodder, USA; O.G. Jonsson, Iceland; D. Krull, USA; A. Lorenzana, Canada; S. Marchevsky, Argentina; C. Sabbaga, Brazil; I. Safi, USA; W.E. Spruce, USA; D.O. Walterhouse, USA; D. Williams, USA; S. Winter, USA; W.C. Owen, USA; R.W. Shore, USA; M. Kelly, USA; D. Abraao, Brazil; B. Morland, England; P. Chitalkar, India; J.M. Hilden, USA; J. Murray, USA; F. Pedrosa, Brazil; J. Halton; A.A.K. Zaluska, Poland; B. deCamargo, Brazil; M.W. Ben Arush, Israel; R.K. Goyal; M.M. Silva, Brazil; M. Arnaout, Jordan; R. Klaassen, Canada; B.L. Pizer, England; and A. Abdelmonem, USA.
The authors indicated no potential conflicts of interest.
Supported in part by grants CA-21765 and CA-71907 from the National Institutes of Health (US Department of Health and Human Services), a Center of Excellence grant from the State of Tennessee, the Conselho Nacional de Pesquisa (CNPq) of Brazil, and the American Lebanese Syrian Associated Charities (ALSAC). Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 or Fisher's exact test, when appropriate. Continuous variables were compared using the Mann-Whitney test. Complete remission was defined as complete (macroscopic and microscopic) tumor resection, absence of distant metastasis, and normalization of all laboratory values. 
13 years (ratio, 6.2:1). In the 4- to 12-year-old group, neither sex predominated (
