Review
The International Pediatric Adrenocortical Tumor Registry initiative: Contributions to clinical, biological, and treatment advances in pediatric adrenocortical tumors

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Abstract

Adrenocortical tumor (ACT), a rare tumor with a heterogeneous presentation, incompletely understood pathogenesis, and generally poor prognosis, occurs in 1–2 people per million and is even more uncommon in the pediatric population. Such rare cancers are a challenge to clinical practice. Exchange of experience, information, and data on rare cancers is lacking, and outcomes for these rare cancers could be improved through the establishment of an international registry. The establishment of the International Pediatric Adrenocortical Tumor Registry (IPACTR) in 1990 by the St. Jude Children’s Research Hospital International Outreach Program offered a new opportunity to collect clinical and laboratory features, treatment practices, and outcome data for children with ACT, research this disease, and systematically investigate how to improve patient outcomes. These efforts will improve the availability of information for both patients and the medical community.

Highlights

► Concept of rare childhood malignancies. ► Pediatric adrenocortical tumor as a model for rare diseases. ► Importance of a registry as a strategy to advance treatment and understanding of rare diseases. ► Development of the St. Jude International Pediatric ACT Registry (IPACTR). ► Children’s Oncology Group (COG) protocol for pediatric adrenocortical tumors.

Introduction

Malignancies in children and adolescents are rare. The risk of a child developing cancer before age 15 is estimated to be 1 in 600 (Stiller, CA, 1992). Therefore, pediatric and adolescent malignancies account for only about 1–2% of all human malignancies (Coleman et al., 1999). The number of newly diagnosed cases of pediatric malignancies is about 12,400 per year in individuals younger than 20 years in the United States (Ries et al., 1999). Childhood malignancies differ clinically, histopathologically, and biologically from those in adults (Miller et al., 1995), suggesting that diverse tumorigenic mechanisms operate in the pediatric and adult populations. Several types of malignancies, especially those of embryonic origin, are virtually restricted to the pediatric age group. Conversely, carcinomas of the lung, female breast, stomach, large bowel, and prostate, which account for the majority of those seen in adults, are extremely rare in childhood and early adolescence (Moschovi et al., 2010, Stiller and Draper, 1989).

The concept of disease rarity has been a matter of controversy. According the Orphan Drug Act, rare diseases are those that affect fewer than 200,000 people in the United States, and, as such, there is no expectation that the cost of developing and making drugs available to treat rare diseases would be recovered from drug sales (Rare Disease Act of 2002: Public law act 107–280 November 6, 2002. http://history.nih.gov/research/downloads/PL107-280.pdf). According to the European Union, a medical condition is defined as rare when it affects fewer than 5 individuals per 10,000 population (Orphan Drug Regulation 141/2000 and Council Recommendation, of 8 June 2009, on an action in the field of rare diseases). Based on these criteria, pediatric cancers as a group can be considered rare. Moreover, pediatric malignancies are heterogeneous, and some subtypes affect fewer than 1 per million children. These very rare malignancies, including adrenocortical tumor (ACT), have been classified as “others” in tallies of pediatric malignancies and usually are not subjects of clinical and laboratory studies (Pappo et al., 2010). In addition, many of the rare malignancies are unique to the pediatric age group and may not have adult counterparts. Therefore, children with very rare malignancies do not have access to evidence-based treatment, and families lack information on the diseases’ natural history, prognosis, and outcome.

Many of these aggressive embryonic tumors are associated with germline, de novo, or somatic gene mutations that were acquired early during embryogenesis (MacDonald, 2008). It can be assumed that genetic changes involved in malignant transformation during developmental phases are potent tumor-initiating events and do not require many other collaborating genetic changes, such as those involved in adult tumorigenesis, including environmental and endogenous changes from aging. Until recently, pediatric embryonal malignancies were usually fatal; hence, most affected individuals did not reach their reproductive age. Consequently, constitutional mutations predisposing individuals to embryonal tumors were selected to be eliminated from the human genetic pool. Therefore, their role in collaborating with other environmentally determined and spontaneously occurring genetic changes could not be appreciated in adult tumorigenesis. As treatment of children with embryonal pediatric malignancies became more effective, many of the long-term survivors were noted to have an increased propensity to adult-type tumors, implicating these constitutional genetic changes in tumorigenesis of both embryonal and adult tissues. Patients with retinoblastoma are the prototype example of individuals who survive an embryonal tumor in infancy but continue to be at high risk for other tumor types at older ages (Dyer et al., 2005). Therefore, despite their rarity, the study of selected pediatric malignancies, particularly of those of embryonal nature, provides unique opportunities to identify cell pathways implicated in tumorigenesis in general. However, there are major challenges to studying very rare tumors. First, a large number of cases is necessary for meaningful studies. Second, specific uniform treatment protocols are required for survival and prognostic factor analysis. Third, for carriers of constitutional mutations, long-term follow-up of affected children and updated information on their relatives in the mutation-segregating parental line are required. Finally, biological materials from these tumors are essential for genotype–phenotype correlative analysis. Rare tumor registries can overcome many of the challenges associated with low patient numbers, irregular treatment management, and lack of follow-up information and tumor tissue. Furthermore, rare tumor registries can generate invaluable information about the tumors’ natural history and create opportunities for translational research, resulting in better treatment for very rare cancers. In this chapter, we describe the activities of the International Pediatric Adrenocortical Tumor Registry (IPACTR).

Section snippets

Pediatric adrenocortical tumor

In the United States, Surveillance, Epidemiology and End Results (SEER) data from the National Cancer Institute show only about 1.3% of all childhood malignancies are carcinomas, and about 0.2% are ACT. Only about 25 new cases of ACT are expected to occur annually in the United States (Altekruse et al., 2010). Unlike pediatric carcinomas in general, which show a progressive increase in incidence with age, ACT has a peak incidence between ages 1 and 4 years. The estimated incidence of ACT is 0.4

IPACTR-1

By the late 1980s, it was clear that there was a cluster of pediatric ACT in several southern states of Brazil (Ribeiro et al., 1990). In fact, by examining the medical files of a charity hospital in São Paulo, Marigo and collaborators (1968) raised this possibility as early as 1968. The comparison of the clinical manifestations and outcome of children with ACT admitted to a single institution in Southern Brazil and those reported in France (Lefevre et al., 1983) and other small series from

Children’s Oncology Group Adrenocortical Tumor Trial

Cooperative, multi-institutional efforts have been pivotal in the advancement of pediatric oncology during the past several decades. Rare pediatric tumors, however, have remained research orphans, and children with these rare malignancies have yet to benefit from group initiatives. The merger of the Pediatric Oncology Group, Children’s Cancer Study Group, and the National Wilms Tumor Study Group into the Children’s Oncology Group (COG) in 2000 offered a unique opportunity to overcome these

Acknowledgments

The authors wish to thank David Galloway for reviewing and editing the manuscript content.

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    This work was supported in part by Grant CA-21765 from the National Institutes of Health (U.S. Department of Health and Human Services), by a Center of Excellence grant from the State of Tennessee, and by the American Lebanese Syrian Associated Charities (ALSAC).

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