ReviewThe International Pediatric Adrenocortical Tumor Registry initiative: Contributions to clinical, biological, and treatment advances in pediatric adrenocortical tumors☆
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.
References (58)
- et al.
The Italian registry for adrenal cortical carcinoma: analysis of a multiinstitutional series of 129 patients. The ACC Italian registry study group
Surgery
(1996) - et al.
The challenge of very rare tumours in childhood: the Italian TREP project
Eur. J. Cancer
(2007) - et al.
Adrenal cortical tumors in children: factors associated with poor outcome
J. Pediatr. Surg.
(2011) - et al.
Surgical management, DNA content, and patient survival in adrenal cortical carcinoma
Surgery
(1995) - et al.
Classical osteoblastoma, atypical osteoblastoma, and osteosarcoma: a comparative study based on clinical, histological, and biological parameters
Clinics (Sao Paulo)
(2007) - et al.
Familial predisposition to adrenocortical tumors: clinical and biological features and management strategies
Best Pract. Res. Clin. Endocrinol. Metab.
(2010) - et al.
Childhood adrenocortical tumours
Eur. J. Cancer
(2004) - et al.
A surgical approach to adrenocortical tumors in children: the mainstay of treatment
J. Pediatr. Surg.
(2004) Classification of adrenal cortical tumors: what limits for the pathological approach?
Best Pract. Res. Clin. Endocrinol. Metab.
(2010)- et al.
The impact of tumor stage on prognosis in children with adrenocortical carcinoma
J. Urol.
(2005)
Are there low-penetrance TP53 Alleles? Evidence from childhood adrenocortical tumors
Am. J. Hum. Genet.
Adrenocortical carcinoma: clinical update
J. Endocrinol. Metab.
Association of the germline TP53 R337H mutation with breast cancer in southern Brazil
BMC cancer
Correlation of pathologic features with clinical outcome in pediatric adrenocortical neoplasia. A study of a Brazilian population. Brazilian group for treatment of childhood adrenocortical tumors
Am. J. Clin. Pathol.
Increased incidence of choroid plexus carcinoma due to the germline TP53 R337H mutation in southern Brazil
PLoS ONE
Long-term (15 Years) outcome in an infant with metastatic adrenocortical carcinoma
J. Clin. Endocrinol. Metab.
Neoplasms of the adrenal cortex. Preoccupation bordering on obsession
Am. J. Clin. Pathol.
Use of preclinical models to improve treatment of retinoblastoma
PLoS Med.
Adrenocortical carcinoma: a clinician’s update
Nat. Rev. Endocrinol.
Penetrance of adrenocortical tumours associated with the germline TP53 R337H mutation
J. Med. Genet.
Follow-up study of twenty-four families with Li–Fraumeni syndrome
Cancer Res.
Beyond Li–Fraumeni Syndrome: clinical characteristics of families with p53 germline mutations
J. Clin. Oncol.
Multiple primary cancers in families with Li–Fraumeni syndrome
J. Natl. Cancer Inst.
Adrenocortical carcinoma in children: a role for etoposide and cisplatin adjuvant therapy? Preliminary report
Med. Pediatr. Oncol.
An inherited mutation outside the highly conserved DNA-binding domain of the p53 tumor suppressor protein in children and adults with sporadic adrenocortical tumors
J. Clin. Endocrinol. Metab.
Adrenal cortical carcinoma in children: 42 patients treated from 1958 to 1980 at Villejuif
Cited by (0)
- ☆
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).