ELSEVIER
Molecular and Cellular Endocrinology
journal homepage: www.elsevier.com/locate/mce
Mediculse soud Celular Endocrinology
Review
The International Pediatric Adrenocortical Tumor Registry initiative: Contributions to clinical, biological, and treatment advances in pediatric adrenocortical tumors
Raul C. Ribeiro a,b, Emilia M. Pinto a,c,*, Gerard P. Zambetti , Carlos Rodriguez-Galindo d
a International Outreach Program, St. Jude Children’s Research Hospital, Memphis, TN, USA
b Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA
“Department of Biochemistry, St. Jude Children’s Research Hospital, Memphis, TN, USA
d Dana-Farber Cancer Institute/Boston Children’s Hospital, USA
ARTICLE INFO
Article history: Available online 23 October 2011
Keywords:
Rare disease
Adrenocortical tumor Pediatric Adrenocortical Tumor Registry TP53 mutation Arg337His
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 uncom- mon in the pediatric population. Such rare cancers are a challenge to clinical practice. Exchange of expe- rience, 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.
@ 2011 Elsevier Ireland Ltd. All rights reserved.
Contents
1. Introduction
2. Pediatric adrenocortical tumor
37 38
3. International Pediatric Adrenocortical Tumor Registry (IPACTR)
39
3.1. IPACTR-1
39
3.2. IPACTR-2
40 41
4. Children’s Oncology Group Adrenocortical Tumor Trial Acknowledgments
42
References
42
1. 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 malignan- cies 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). Child- hood malignancies differ clinically, histopathologically, and biolog- ically 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
** * 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).
* Corresponding author. Address: International Outreach, MS 721, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105- 2794, USA. Tel .: +1 901 595 5318; fax: +1 901 595 5319.
E-mail address: emilia.pinto@stjude.org (E.M. Pinto).
seen in adults, are extremely rare in childhood and early adoles- cence (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 popula- tion (Orphan Drug Regulation 141/2000 and Council Recommen- dation, of 8 June 2009, on an action in the field of rare diseases). Based on these criteria, pediatric cancers as a group can be consid- ered 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 embryo- nal malignancies were usually fatal; hence, most affected individu- als did not reach their reproductive age. Consequently, constitutional mutations predisposing individuals to embryonal tu- mors 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 tis- sues. Patients with retinoblastoma are the prototype example of individuals who survive an embryonal tumor in infancy but con- tinue 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 proto- cols are required for survival and prognostic factor analysis. Third, for carriers of constitutional mutations, long-term follow-up of af- fected 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 treat- ment 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 opportuni- ties for translational research, resulting in better treatment for very rare cancers. In this chapter, we describe the activities of the Inter- national Pediatric Adrenocortical Tumor Registry (IPACTR).
2. 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 pedi- atric 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 per million dur- ing the first 4 years of life, and it decreases to 0.1 per million during the subsequent 10 years. It then rises to 0.2 per million during the late teens and reaches another peak during the fifth decade of life. This pattern is consistent with the concept that ACT comprises at least two distinct groups in the first two decades: the first peak represented by tumors arising from the fetal (embryonal) adrenal gland and the other peak represented by those arising from the cortex of the definitive adrenal gland (Michalkiewicz et al., 2004). Worldwide, the incidence of ACT differs across geographic regions. The reported incidence per million children younger than 14 years ranges from 0.1 in Hong Kong and Bombay to 0.4 in Los Angeles to 3.4 in Southern Brazil (Ribeiro and Figueiredo, 2004).
On the basis of case reports of sporadic ACT in multiple siblings and the familial occurrence of ACT accompanied by diverse other neoplasms, Miller (1968) first suggested that pediatric ACT had a genetic basis. Clustering of ACT was also noted in other multisys- temic constitutional pediatric syndromes such as Beckwith- Wiedemann syndrome (BWS), multiple endocrine neoplasia (MEN) type 1, Carney’s complex, congenital adrenal hyperplasia, and hemihypertrophy syndrome (Ribeiro et al., 2010). However, only a minority of children with ACT have one of these constitu- tional syndromes.
In the late 1960s, Li and Fraumeni described four families with an autosomal-dominant cancer distribution pattern. In these fam- ilies, siblings or cousins had childhood sarcoma and a high concen- tration of cancers in relatives, especially soft tissue sarcomas and breast carcinomas (Li and Fraumeni, 1969). Except for an increased predisposition to cancer at a young age, patients and relatives did not have any congenital malformations or other constitutional abnormalities. Subsequently, these investigators examined the files of the Cancer Family Registry of the National Cancer Institute for families with sarcoma, breast cancer, and other neoplasms occurring in children and young adults (Li et al., 1988). Eligibility for the study was restricted to families with three close relatives who had had cancer. All of the 24 families studied had a case of sarcoma before age 45 designated as the proband, a first-degree relative with cancer in this age interval, and another first- or sec- ond-degree relative in the lineage with cancer at this age interval or a sarcoma at any age. The primary findings in their 24 study families and those of an additional 21 families in works already published by other researchers revealed an autosomal dominant pattern of diverse neoplasms in children and young adults; a predominance of soft tissue sarcomas, osteosarcoma, and breast cancer; an excess of brain tumors, leukemia, and adrenocortical carcinoma (ACC); and the occurrence of multiple primary neo- plasms in young individuals. Remarkably, among 44 malignancies occurring in children younger than 10 years, 4 cases (9.1%) were ACT. This nonrandom familial aggregation of cancer has been classified as Li-Fraumeni syndrome (LFS) or sarcoma, breast, leu- kemia, and adrenal (SBLA) syndrome. Further studies showed that sarcoma and cancers of the breast, brain, and adrenal glands ac- count for about 80% of all cancers that occur in LFS families. These cancer types have been considered indicative of Li-Fraumeni com- ponent or core cancers and tend to be concentrated in defined age groups. Soft-tissue sarcomas, as well as adrenal and brain tumors,
predominate in children, whereas bone sarcoma is more common in teenagers and breast and brain tumors in young adults (Olivier et al., 2003). Similarly, epidemiologic data corroborate that ACT ac- counts for about 10% of the pediatric cancers occurring in Li-Frau- meni families (Garber et al., 1991; Gonzalez et al., 2009; Hisada et al., 1998). Segregation analysis suggests that the observed cancer distribution best fits a rare autosomal-dominant gene model. In 1990, Malkin and colleagues (1990) screened the TP53 gene for mutations in five of the original families reported by Li and Frau- meni and found germline mutations in exon 7 segregating in the parental line affected with tumors in Li-Fraumeni families. More- over, in Li-Fraumeni families, carriers of TP53 mutations had a 90% probability of cancer during their lifetime (Tabori and Malkin, 2008). However, individuals with cancer in about 20% of Li-Frau- meni families do not carry TP53 mutations, suggesting a role for other genes in determining the Li-Fraumeni syndrome phenotype. Furthermore, individuals of non-Li-Fraumeni syndrome families with certain types of cancer, particularly ACT, sarcomas, and breast cancer, were found carry TP53 mutations. Based on a series of chil- dren with ACT, Varley and colleagues (1999) found germline TP53 mutations in 9 of 14 cases of pediatric ACT selected for TP53 testing without reference to the family’s history of cancer. They suggested the term low-penetrance to highlight that some TP53 mutations are not associated with a pervasive family history of cancer. These observations suggest that the oncogenic potential of TP53 muta- tions might vary depending on the type of mutation. Consistent with this concept, several functional assays of proteins encoded by different TP53 mutations have shown a spectrum of activity. Moreover, it has been increasingly evident that common polymor- phisms of selected genes might modulate the oncogenic potential of p53 (Zambetti, 2007) (Fig. 1).
Persuasive evidence that different TP53 mutations have diverse cancer predisposition potential is the observation of a cluster of ACT in Southern Brazil. It has been known for many years that the incidence of ACT is higher in the southeast region of Brazil, with an annual incidence of 3.4-4.2 per 1 million children (Allolio and Fassnacht, 2006). According to the SEER data, 79 cases of pediatric ACT were reported from 17 geographic areas in the United States during a 34-year period (1973-2007) (Altekruse et al., 2010). Remarkably, the number of cases in the SEER database equals only approximately 60% of the cases treated at a single institution in Southern Brazil (n = 124) (Hospital das Clínicas de Curitiba, Paraná) during a similar time period (37 years) (Pianovski et al., 2006). Explanations for this observation remained elusive until the discov- ery that more than 90% of children with ACT in this region carried a unique founder TP53 mutation (Arg337His) (Latronico et al., 2001; Pinto et al., 2004; Ribeiro et al., 2001). The frequency of this mutation
Tumor Risk
Low
High
Polymorphisms
R337H
P53
Polymorphisms
MDM2
R337C
R175L
R175P
R175H
Signaling Alterations (ARF/ATM/ATR/CHK2)
is about 0.3% in the general population of Paraná (Custodio, 2011). In addition to ACT, an excess of choroid plexus carcinoma, osteosar- coma, breast cancer, and stomach cancer have been noted in Arg337His carriers (Assumpcao et al., 2008; Custodio et al., 2011; Figueiredo et al., 2006; Oliveira et al., 2007; Seidinger et al., 2010). In about 30% of families of children with ACT, the parental line seg- regating the Arg337His in multiple generations does not have other cancer cases. In about 40% of these families, the Li-Fraumeni-like phenotype has been observed. Breast and brain tumors are the most common cancer types in these families. Finally, the remaining families have an apparent increase in sporadic tumors that are not typ- ical of any known familial cancer syndrome (Figueiredo et al., 2006).
Until 1990, the natural history, treatment, and outcome of chil- dren with ACT were essentially unknown. Classic pediatric oncol- ogy textbooks contained a one-page description of the disease. Disease stage classification, histopathologic criteria, and prognosis were based on ACT in adults. Small case series of pediatric ACT had been published, describing the clinical and histopathologic fea- tures and highlighting the poor outcome of these patients (Klein et al., 2011; Ribeiro and Figueiredo, 2004), particularly those with advanced-stage disease. Surgery, chemotherapy, and mitotane were suggested for the management of some of these patients. Between 1990 and 2000, after the association between TP53 muta- tions and pediatric ACT was established and the cluster of ACT cases carrying a low-penetration mutant was reported, researchers began to consider a specific ACT registry to obtain data to deter- mine the clinical biological characteristics, management, progno- sis, and outcome of a large group of pediatric patients.
3. International Pediatric Adrenocortical Tumor Registry (IPACTR)
3.1. IPACTR-1
By the late 1980s, it was clear that there was a cluster of pedi- atric 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 around the world showed no differences, suggesting that, despite diverse geographic, ethnic, environmental, and possibly genetic characteristics, pediatric ACT appears to have a consistent clinical and biological course. In 1990, one of the authors of this work (RCR), proposed the creation of a pediatric ACT registry to better define the clinical manifesta- tions, prognosis, treatment, and outcome of pediatric ACT. Between January 1990 and December 2001, 254 cases were registered in a disease-specific database (IPACTR-1) (Michalkiewicz et al., 2004). About 80% of the cases were from Southern Brazil, although 10 other countries were also represented. Most of the cases (n = 228) were classified as carcinoma, and the remaining 26 were classified as adenoma. The median age of the 156 girls and 98 boys was 3.2 years. Girls predominated in the age group 0-3 years (ratio, 1.7:1) and ≥13 years (ratio, 6.2:1). In the 4- to 12-year- old group, neither sex predominated (ratio, 0.8:1). Virilization alone or in combination with signs of overproduction was the most common presenting endocrine syndrome. Isolated Cushing’s syn- drome was rare, as well as Conn’s syndrome. About 10% of the pa- tients had nonfunctional tumors. About 75% of the patients had stage I or stage II disease. Among patients with advanced disease, 25 patients (9.8%) had stage III and 37 (14.6%) patients had stage IV disease. Stage I disease required that patients had completely resected tumors of less than 200 g and absence of local residual
or metastatic disease. Stage II disease was defined the same as stage I disease but with tumors 200 g or greater. Stage III disease indicated that the patients had microscopic residual disease, and stage IV disease included distant metastasis. Surgery for primary resection was attempted in all patients. Adjuvant treatment was administered in 7 of 116 patients with stage I disease (5 patients, mitotane; 1 patient, radiotherapy; and 1 patient, combination che- motherapy), and 16 of those with stage II disease (13 patients, mitotane; 2 patients, combination chemotherapy; 1 patient, radio- therapy). All patients with stage III or IV disease received chemo- therapy, usually a combination of cisplatin, etoposide, and mitotane. At the time of the report, 157 patients (61.8%) were alive, and 97 patients (38.2%) had died (Michalkiewicz et al., 2004). All deaths except 5 were due to progressive disease. The 5-year event-free survival (EFS) estimates were 54.2% (95% CI, 48.2- 60.2%). For patients who had completely resected disease (disease stages I and II), prognostic factor analysis showed that stage I disease, age less than 3 years, and virilization alone were independently associated with a good prognosis. All these groups had 5-year EFS estimates greater than 85%. Conversely, for children with metastatic or residual disease, the prognosis was dismal. Because histologic parameters associated with a poor prognosis have been controversial in ACT (Bugg et al., 1994; Dehner, 1994; Tissier, 2010; Weiss, 1984), they were not included in the prognos- tic factor analysis. Nonetheless, of 26 cases classified as adenoma, only 1 patient had a relapse.
Although IPACTR-1 has provided valuable insights into the nat- ural history of pediatric ACT, prognostic indicators, and current management practices, it could not yield recommendations about treatment because the number of patients treated was small. In addition, certain events such as tumor spillage and lymph node involvement were not systematically studied in IPACTR-1.
Treatment of childhood ACT has evolved from the data derived from adult studies, and the same guidelines are used; surgery is the most important mode of therapy, and mitotane and cisplatin-based regimens are recommended for patients with advanced disease (Hovi et al., 2003; Rodriguez-Galindo et al., 2005; Zancanella et al., 2006; Fassnacht et al., 2011). An aggressive surgical approach of the primary tumor and all metastatic sites is recommended when feasible (Stewart et al., 2004; Tucci et al., 2005). Because of tumor friability, rupture of the capsule with resultant tumor spill- age is frequent (approximately 20% of initial resections and 43% of resections after recurrence) (Michalkiewicz et al., 2004; Sandrini et al., 1997). In fact, spontaneous tumor rupture resulting in acute abdomen as presentation of pediatric ACT has been described (Leung et al., 2002). Therefore, a laparoscopic approach in children sus- pected to have ACT should be avoided. The lymph node drainage of the adrenal gland is complex. There is an extensive subserosal network of lymphatic channels around the gland, crossing several levels in different directions inside the fascia and connective tissue involving the adrenal gland. The incidence of lymph node involve- ment is not known, although some studies report it to be close to 40% in adults (Crucitti et al., 1996; Lee et al., 1995). In children, available data suggest that nodal involvement is present in approx- imately 30% of the cases. Whether ipsilateral retroperitoneal lymph node dissection may improve local control is a matter of de- bate. Chemotherapeutic regimens used for patients with advanced disease have derived from the standard treatments used in adults. A cisplatin-based combination, usually incorporating doxorubicin and etoposide, is most commonly used (Rodriguez-Galindo et al., 2005; Zancanella et al., 2006). Little information is available about the use of mitotane in children, although response rates appear to be similar to those seen in adults. There have been several reports of complete responses in children with advanced or metastatic ACT, but these appear to be rare events (Terzolo et al., 2007). In a review of 11 children with advanced ACT treated with mitotane
and a cisplatin-based chemotherapeutic regimen, measurable responses were seen in seven patients. The mitotane daily dose required for therapeutic levels was around 4 g/m2, and therapeutic levels were achieved after 4-6 months of therapy (Zancanella et al., 2006). Compliance with daily mitotane administration is a major limitation to therapy in young children; nausea, vomiting, diar- rhea, and neurologic alterations are common (Zancanella et al., 2006). Monitoring for neurotoxicity is particularly important in young patients, as the use of mitotane has been associated with de- lays in motor and speech development (De Leon et al., 2002).
3.2. IPACTR-2
The discovery that children with ACT from Southern Brazil car- ried a specific TP53 Arg337His mutation, but that their relatives in the mutation-segregating parental line did not show the cancer pro- file expected in Li-Fraumeni syndrome families, raised the possibil- ity that adrenal tissue is more permissive to p53-driven malignant transformation. This concept is consistent with findings of func- tional p53 assays showing that some inherited TP53 mutations detected in children with ACT (Arg337His, Arg175Leu) exhibit dif- ferent transactivation activity than those with TP53 mutations detected in carriers of Li-Fraumeni syndrome. In addition, several reports have indicated that pediatric ACT often is the first manifes- tation of an inherited germline TP53 mutation in a family or kindred (Varley et al., 1999; West et al., 2006). Based on these and other observations, we made the following assumptions in amending the IPACTR protocol: (i) about two thirds of pediatric ACT is associated with TP53 mutations, (ii) ACT develops in approximately 5-10% of individuals carrying a constitutional TP53 mutation during first decade of life, (iii) less than 50% of children with p53-associated ACT are from classic Li-Fraumeni syndrome families, and (iv) in fam- ilies of children with ACT who inherited a germline TP53 mutation, the mutation-segregating parental line shows an excess of various cancer types compared with that in the contralateral parental line. To examine these assumptions, we amended the IPACTR protocol to attempt to characterize clinically, epidemiologically, and molec- ularly the largest possible number of pediatric ACT cases, including both prospective and retrospective cases. The changes in the IPACTR 2 protocol include: (i) obtaining informed consent by telephone di- rectly from parents of children with ACT; (ii) offering TP53 testing for patients and parents; (iii) centralizing histopathologic review for all cases enrolled on the study; (iv) updating the family history of can- cer annually; and (v) enrolling on the study patients’ relatives in the mutation-segregating parental line who develop cancer. In many in- stances, the IPACTR protocol adds information to that generated by Children’s Oncology Group because the IPACTR allows retrospective patient registration. From 2002 to June 2011, 67 children and ado- lescents with ACT and two relatives (with breast cancer and renal cell carcinoma) from the United States and other countries (Argen- tina, Brazil, Colombia, Dubai, England, Greece, Honduras, Spain, and United Arab Emirates) have been enrolled. The clinical and laboratory characteristics of this group are very similar to those de- scribed for the IPACTR-1 patients. Beckwith-Wiedemann syndrome was observed in 1 child. Li-Fraumeni syndrome was observed in 9 cases (13.4%). In 17 ACT cases, no biological samples were available. To date, the TP53 status has been determined in 50 pediatric ACT cases. Tumor tissue DNA was available in 45 ACT cases. The wild- type (WT) TP53 sequence was observed in 13 cases (28.8%). In the remaining 32 (71.2%), TP53 mutations were noted. Somatic TP53 mutations were observed in 4 cases, all of them in a heterozygous state, and germline TP53 mutations in 24 ACT cases. In the remaining 4 ACT cases with TP53 mutations, it was not possible to define whether the TP53 mutations were somatic or germline mutations because paired blood was not available. Of the 15 germline muta- tions cases in which patient and parental blood DNA was available
c.151_156 del CCGCCCGGCACCC
IVS4+1G/A
c. 134_135 insT
c.108_110 dupl GTTTCCG
IVS10 - 2A/G
c51_53 del CAAT ins GACCTG
R196X
1
2
3
4
5
6
7
8
9
10
11
G245C
R248W
R213Q
V157F
G266E
I332F
R158L
R273C
G334R
R175L
R273H
R337C
R175H
R282W
R337H
R283H
E285V
TAD
Pro-rich
DBD
NLS TET Basic
for study, 10 cases were inherited and 5 were de novo TP53 muta- tions. In 9 germline TP53 cases, blood from parents was not accessed to define inheritance. In 5 ACT cases, only patient blood was avail- able, and all of them had the WT TP53 sequences. Loss of heterozy- gosity was observed in 21 cases tested with a TP53 mutation and in 4 cases with the WT TP53 sequence. There were 24 different TP53 mutations observed in our cohort, and only 3 were reported more than once (Arg337His, Arg175His, and Arg273Cys). Two muta- tions, the TP53 Ile332Phe and Gly334Arg, both located in the tetra- merization domain of p53, have not been previously reported. These mutations occurred through the TP53 gene, and no hot spot site was evident (Fig. 2). The observations from IPACTR-2 have cor- roborated the assumptions that the detailed study of pediatric ACT may provide important clues regarding the role of p53 in diverse hu- man malignancies.
4. 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 Oncol- ogy 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 obstacles
(Pappo et al., 2010). In 2002, the COG created the rare tumor com- mittee, which currently integrates subcommittees on liver tumors, germ cell tumors, retinoblastoma, and infrequent tumors. The main objectives of the infrequent tumor subcommittee were to create an organizational framework to facilitate the study of these infrequent malignancies and to develop registries, biospecimen banks, and clinical trials. Building from the experience of IPACTR, the COG rare tumor committee sought to encourage registration of all pediatric rare cancers into the COG research registry. Based on the estimates from the SEER database, 71% of the expected cases of ACC were registered, which compares very favorably with other pediatric rare tumors such as melanoma (14%) and retinoblastoma (38%); while these data are very encouraging, they continue to highlight the obstacles in the development of clinical research in very rare cancers (Pappo et al., 2010). A more ambitious goal was to develop an ACC-specific protocol that would offer an opportu- nity to integrate clinical and biological research. This resulted in the development of the ARAR0332 protocol (Treatment of Adreno- cortical Tumors with Surgery plus Lymph Node Dissection and Multiagent Chemotherapy), a collaboration between COG and Brazilian institutions. This protocol investigates three main clinical questions: (1) the efficacy of surgery alone for stage I tumors (dis- ease stage system, Table 1); (2) the role of retroperitoneal lymph node resection in reducing local recurrence of stage II tumors; and (3) the impact of mitotane and cisplatin-based chemotherapy for unresectable and metastatic disease (Table 2).
| Stage | Definition |
|---|---|
| I | Completely resected, small tumors (<100 g and <200 cm3) with normal postoperative hormone levels |
| II | Completely resected, large tumors (≥100 g or ≥200 cm3) with normal postoperative hormone levels |
| III IV | Unresectable, gross or microscopic residual disease Tumor spillage Patients with Stage I and II tumors who fail to normalize hormone levels after surgery Patients with retroperitoneal lymph node involvement |
| Presence of distant metastases |
| Stage | Treatment |
|---|---|
| Stage I | Surgery alone |
| Stage II | Surgery |
| RPLN dissection | |
| Stage III | Mitotane CDDP/ETO/DOX |
| Surgery + RPLN dissection | |
| Stage IV | Mitotane CDDP/ETO/DOX |
| Surgery + RPLN dissection |
Abbreviations: RPLN, retroperitoneal lymph node; CDDP, cisplatin; ETO, etoposide; DOX, doxorubicin.
The ARAR0332 protocol also attempts to provide further insight into the biology of ACT and the different patterns of TP53 muta- tions. The protocol opened in August 2006 in the North American institutions and in June 2008 in the two institutions in Southern Brazil. Sixty patients have been enrolled as of July 2011. Impor- tantly, more than one third of the patients enrolled are from the ACT cluster area in Southern Brazil, which highlights the impor- tance of collaborative studies for pediatric ACT and will allow gath- ering a significant amount of data to better define the clinical characteristics, treatment, and outcomes for children with ACT and to increase our knowledge of its biology and epidemiology. Similar initiatives aimed at establishing cancer registries and developing treatment guidelines for pediatric rare cancers, includ- ing ACT, are also being developed in Europe, as exemplified by the Italian Tumori Rari in Età Pediatrica (TREP; Rare Tumors in Pediat- ric Age) project (Ferrari et al., 2007). Initiatives that coordinate ef- forts in pediatric ACC are clearly needed. It is only through the development of international collaborative projects that we can further our knowledge of the epidemiology and biology of this neoplasm.
Acknowledgments
The authors wish to thank David Galloway for reviewing and editing the manuscript content.
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