The annual incidence of cancer in the United States is estimated to be 1 in 7000 in children younger than 15 years of age [Surveillance Epidemiology and End Results Program (SEER) data 1990 to 1997].1 Thus, every year, 12,000 children and adolescents less than 20 years old are diagnosed with cancer. Since the 1970s, remarkable progress has been made in the understanding, management, and outcome of common pediatric malignancies through the efforts of cooperative groups such as the Children’s Oncology Group (COG). Survival for children with acute lymphoblastic leukemia has markedly improved, and the overall survival for children with this hematological malignancy is now approximately 80%. However, for the less common pediatric malignancies (rare tumors), such progress has not been achieved.
WHAT CONSTITUTES A RARE PEDIATRIC TUMOR
The definition of what constitutes a rare pediatric tumor is somewhat arbitrary. Rare diseases are defined by the National Institutes of Health, Office of Rare Diseases as those diseases having a prevalence of <200,000 affected individuals in the United States.2 In Europe, rare diseases are defined as those affecting 1 in 2000 citizens of the European Union.3 By these definitions, all childhood cancers are rare. The Italian TREP project defined “rare pediatric tumors” as any solid malignancies characterized by an annual incidence <2 per million and not considered in any other clinical trials.4 However, on the basis of the data from the SEER registry of the National Cancer Institute, this definition would exclude the 2 most common rare tumors seen in children and adolescents, thyroid carcinoma and melanoma, whose incidence rates are 4.9 and 4.6 per million, respectively, in children younger than 20 years of age.5 Hence, in the COG Rare Tumor Committee, we chose to define infrequent tumors within the context of a pediatric population as those neoplasms that are generally classified as other malignant epithelial neoplasms and melanomas in the International Classification of Childhood Cancer subgroup XI of the SEER database.6 Thus, a large number of tumors with a varied biology and clinical presentation were included in the rare tumor group. The tumors included were thyroid carcinomas, colorectal carcinomas, melanomas, gastrointestinal stromal tumors, gonadal stromal tumors, pancreatoblastoma, carcinoid tumors, desmoplastic small round cell tumors, nasopharyngeal carcinomas, and adrenocortical carcinomas. Other tumors that are rare, but were not included as they have their own clinical trials, are malignant germ cell tumors, hepatoblastoma, renal rhabdoid tumors, and rare histiotypes of soft tissue sarcomas.
Although rare as individual tumors, in aggregate, these tumors account for 15% of all cancers in children younger than 20 years and 30% of all tumors in children between the ages of 15 and 19 years.1
CHALLENGES ASSOCIATED WITH RARE TUMORS
There are considerable challenges associated with studying rare tumors. Small numbers of individual tumors make basic and clinical research difficult. It is also difficult to obtain funding for rare tumors when competing with more common cancers, where trials can be completed in a much shorter time. Hence, currently, our knowledge of the clinical presentation, management, and long-term outcome of these tumors is based on limited single-institution data or from extrapolation from adult studies. There are no uniform treatment guidelines or protocols for these rare tumors in children. Many oncologists rarely see patients with these tumors and are faced with a dilemma when confronted with these patients.
RARE TUMOR REGISTRIES
To overcome some of the difficulties mentioned and improve our understanding of rare pediatric tumors, several efforts have been made over the years. Rare tumor registries have been developed both for individual tumors and for combined cooperative group rare tumor registries. Some of the rare tumor registries currently available are outlined in Table 1.
The individual rare tumor registries have significantly improved our understanding of these rare tumors. The Pleuropulmonary Blastoma Registry was founded in 1970 at the University of Minnesota, and has made some critical observations, which have improved our understanding of the molecular pathogenesis of this tumor. They found that 11 muliplex pleuropulmonary blastoma families had germline heterozygous mutation in DICER 1, a gene encoding an endoribonuclease critical to the generation of small noncoding regulatory RNA’s.7 Another registry that has helped our understanding of a rare tumor is the International Pediatric Adrenocortical Tumors Registry. The incidence of adrenocortical carcinoma is 10 to 15 times higher in Southern Brazil. The work conducted by International Pediatric Adrenocortical Tumors Registry investigators led to the discovery of a unique TP53 germline mutation in the tetramerization domain (R337H) that is highly prevalent in Southern Brazil and that seems to predispose one to adrenocortical carcinoma, and less to other cancers that are typical of other more common TP53 mutations.8
At the cooperative group level, the Italian Rare Tumor Registry (TREP project) was launched in 2000 under the auspices of Associazione Italiana Ematologia Oncologia Pediatrica and Societe Internationale d'Oncologie Pediatrique. Thirty-six Italian centers are participating and have enrolled 336 patients (261 children and 75 adolescents) between 2000 and 2006. The project has published their incidence rates comparing them with the Italian Network of cancer registries and found that there was significant underreporting of patients in the adolescent age group.
The German Society of Pediatric Oncology and Hematology established a Rare Tumor Group in 2006, and a clinical registry including German, Austrian, and Swiss groups was launched in 2008.9
COG RARE TUMOR GROUP
The COG Rare Tumor Initiative was developed in 2002. Three subcommittees were established— germ cell, liver, and infrequent tumors. In 2008, the Retinoblastoma and Rare Tumors Committees merged into the current Rare Tumors Committee. The efforts of the infrequent tumor subcommittee were primarily directed towards education and development of feasible and novel multidisciplinary single-arm protocols that could maximize the likelihood of success. The 4 major goals of this subcommittee were (1) to design and implement a group-wide banking study; (2) to develop a Rare Tumor Registry; (3) to develop therapeutic approaches for several rare tumors; and (4) to either develop clinical trials in collaboration with adult co-operative groups or adopt a novel trial strategy such as developing international collaborations.5 The subcommittee has achieved 3 of these aims, with the initiation of the ABTR01B1 banking study, the development of prospective clinical trials with biological aims for adrenocortical carcinoma and nasopharyngeal carcinoma, and the development of therapeutic approaches for several rare tumors.
DEVELOPMENT OF A THERAPEUTIC APPROACH FOR RARE TUMORS
One of the major goals of the infrequent tumor subcommittee was to develop diagnostic and therapeutic recommendations for select rare tumors, by summarizing current literature reviews. These recommendations would help the treating clinicians to care for patients with rare tumors. To develop these recommendations, a Working Group was established. This group consisted of pediatric oncologists, surgeons, pathologists, and radiation oncologists. A total of 8 rare tumors were identified. These included thyroid carcinomas, colorectal carcinoma, melanoma, gastrointestinal stromal tumor, pancreatoblastoma, desmoplastic small round cell tumor, gonadal stromal tumors, and carcinoid. For each tumor, 1 or 2 investigators were identified with expertise in that tumor type. The investigators produced a preliminary document based on a detailed literature review, summarizing the epidemiology, biology, clinical features, and diagnostic and therapeutic recommendations. The document was then reviewed and revised by senior members of the Rare Tumor Steering Committee and the COG Scientific Writers. The final documents are being presented in this journal issue, with the hope and aim that they will help facilitate the dissemination of information regarding these rare tumors to treating clinicians and help them care better for their patients. The authors of each rare tumor guideline also form a network of experts available to treating clinicians to help with the management of these rare tumors.
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8. Ribeiro RC, Sandrini F, Figueiredo B, et al. An inherited p53 mutation that contributes in a tissue specific manner to pediatric adrenal cortical carcinoma. Proc Natl Acad Sci. 2001;98:9330–9335
9. Brecht B, Graf N, von Schweinitz D, et al. Networking for children and adolescents with very rare tumors: foundation of the GPOH pediatric rare tumor group. Klin Padiatr. 2009;221:181–185