Pediatric Germ Cell Tumors: A Developmental Perspective

Germ cell tumors (GCTs) arising in infants, children, and adolescents present a set of special challenges. GCTs make up about 3% of malignancies in children aged 0–18 and nearly 15% of cancers in adolescents. Epidemiologic and molecular evidence suggests that GCTs in young children likely represent a distinct biologic group as compared to GCTs of older adolescents and adults. Despite this difference, pediatric GCTs are typically treated with cisplatin-based multiagent regimens similar to those used in adults. There is evidence that children are particularly vulnerable to late effects of conventional therapy, including ototoxicity, pulmonary abnormalities, and secondary malignancies, motivating the search for molecular targets for novel therapies. Evidence is accumulating that the genes and mechanisms controlling normal germ cell development are particularly relevant to the understanding of germ cell tumorigenesis. Perturbations in the epigenetic program of germ cell differentiation, with resulting effects on the regulation of pluripotency, may contribute to the marked histologic variability of GCTs. Perturbations in the KIT receptor signaling pathway have been identified via next-generation sequencing studies and in genome-wide association studies of testicular cancer susceptibility. Here, we review these and other biological insights that may fuel further translational and clinical research in childhood GCTs

Milk consumption and the prepubertal somatotropic axis

© 2007 Rich-Edwards et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Impact of central surgical review in a study of malignant germ cell tumors

BACKGROUND: Verification of surgical staging has received little attention in clinical oncology trials. Central surgical review was undertaken during a study of malignant pediatric germ cell tumors. METHODS: Children's Oncology Group study AGCT0132 included central surgical review during the study. Completeness of submitted data and confirmation of assigned stage were assessed. Review responses were: assigned status confirmed, assignment withheld pending review of additional information requested, or institutional assignment of stage disputed with explanation given. Changes in stage assignment were at the discretion of the enrolling institution. RESULTS: A total of 206 patients underwent central review. Failure to submit required data elements or need for clarification was noted in 40%. Disagreement with stage assignment occurred in 10% with 17/21 discordant patients reassigned to stage recommended by central review. Four ovarian tumor patients not meeting review criteria for Stage I remained in that stratum by institutional decision. Two-year event free survival in Stage I ovarian patients was 25% for discordant patients compared to 57% for those meeting Stage I criteria by central review. CONCLUSIONS: Central review of stage assignment improved complete data collection and assignment of correct tumor stage at study entry, and allowed for prompt initiation of chemotherapy in patients determined not to have Stage I disease

Global childhood cancer survival estimates and priority-setting: a simulation-based analysis.

BACKGROUND: Accurate childhood cancer survival estimates are crucial for policy makers and clinicians for priority-setting and planning decisions. However, observed survival estimates are lacking for many countries, and when available, wide variation in outcomes is reported. Understanding the barriers to optimising survival can help improve childhood cancer outcomes. We aimed to provide estimates of global childhood cancer survival, accounting for the impact of multiple factors that affect cancer outcomes in children. METHODS: We developed a microsimulation model to simulate childhood cancer survival for 200 countries and territories worldwide, accounting for clinical and epidemiologic factors, including country-specific treatment variables, such as availability of chemotherapy, radiation, and surgery. To ensure model results were consistent with reported survival data, we calibrated the model to estimates from the CONCORD-2 and CONCORD-3 studies using an Approximate Bayesian Computation approach. We estimated 5-year net survival for diagnosed cases of childhood cancer in each country and territory and estimated potential survival gains of seven policy interventions focused on improving treatment availability and delivery (ie, increasing the availability of chemotherapy, radiation, general surgery, neurosurgery, or ophthalmic surgery, reducing treatment abandonment, and improving the quality of care to the mean of high-income countries) implemented in isolation or as packages. FINDINGS: Our model estimated that, for diagnosed cases, global 5-year net childhood cancer survival is currently 37·4% (95% uncertainty interval 34·7-39·8), with large variation by region, ranging from 8·1% (4·4-13·7) in eastern Africa to 83·0% (81·6-84·4) in North America. Among the seven policy interventions modelled, each individually provided small gains, increasing global 5-year net survival to between 38·4% (35·8-40·9) and 44·6% (41·7-47·4). 5-year net survival increased more substantially when policy interventions were bundled into packages that improved service delivery (5-year net survival 50·2% [47·3-53·0]) or that expanded treatment access (54·1% [50·1-58·5]). A comprehensive systems approach consisting of all policy interventions yielded superadditive gains with a global 5-year net survival of 53·6% (51·5-55·6) at 50% scale-up and 80·8% (79·5-82·1) at full implementation. INTERPRETATION: Childhood cancer survival varies widely by region, with especially poor survival in Africa. Although expanding access to treatment (chemotherapy, radiation, and surgery) and addressing financial toxicity are essential, investments that improve the quality of care, at both the health-system and facility level, are needed to improve childhood cancer outcomes globally. FUNDING: Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard TH Chan School of Public Health, Harvard Medical School, National Cancer Institute, SickKids, St Jude Children's Research Hospital, Union for International Cancer Control, Children with Cancer UK Davidson and O'Gorman Fellowship

Scaling up cancer care for children without medical insurance in developing countries: The case of Mexico

Background: In 2006, the Mexican government launched the Fund for Protection Against Catastrophic Expenditures (FPGC) to support financially healthcare of high cost illnesses. This study aimed at answering the question whether FPGC improved coverage for cancer care and to measure survival of FPGC affiliated children with cancer. Procedure A retrospective cohort study (2006–2009) was conducted in 47 public hospitals. Information of children and adolescents with cancer was analyzed. The coverage was estimated in accordance with expected number of incident cases and those registered at FPGC. The survival was analyzed by using Kaplan–Meier survival curves and Cox proportional hazards regression modeling. Results: The study included 3,821 patients. From 2006 to 2009, coverage of new cancer cases increased from 3.3% to 55.3%. Principal diagnoses were acute lymphoblastic leukemia (ALL, 46.4%), central nervous system (CNS) tumors (8.2%), and acute myeloid leukemia (AML, 7.4%). The survival rates at 36 months were ALL (50%), AML (30.5%), Hodgkin lymphoma (74.5%), Non-Hodgkin lymphoma (40.1%), CNS tumors (32.8%), renal tumors (58.4%), bone tumors (33.4%), retinoblastoma (59.2%), and other solid tumors (52.6%). The 3-year overall survival rates varied among the regions; children between the east and south-southeast had the higher risks (hazard ratio 3.0; 95% CI: 2.3–3.9) and 2.4; 95% CI: 2.0–2.8) of death from disease when compared with those from the central region. Conclusion: FPGC has increased coverage of cancer cases. Survival rates were different throughout the country. It is necessary to evaluate the effectiveness of this policy to increase access and identify opportunities to reduce the differences in survival

DNA Methylation Analysis Reveals Distinct Methylation Signatures in Pediatric Germ Cell Tumors

Background: Aberrant DNA methylation is a prominent feature of many cancers, and may be especially relevant in germ cell tumors (GCTs) due to the extensive epigenetic reprogramming that occurs in the germ line during normal development. Methods: We used the Illumina GoldenGate Cancer Methylation Panel to compare DNA methylation in the three main histologic subtypes of pediatric GCTs (germinoma, teratoma and yolk sac tumor (YST); N = 51) and used recursively partitioned mixture models (RPMM) to test associations between methylation pattern and tumor and demographic characteristics. We identified genes and pathways that were differentially methylated using generalized linear models and Ingenuity Pathway Analysis. We also measured global DNA methylation at LINE1 elements and evaluated methylation at selected imprinted loci using pyrosequencing. Results: Methylation patterns differed by tumor histology, with 18/19 YSTs forming a distinct methylation class. Four pathways showed significant enrichment for YSTs, including a human embryonic stem cell pluripotency pathway. We identified 190 CpG loci with significant methylation differences in mature and immature teratomas (q \u3c 0.05), including a number of CpGs in stem cell and pluripotency-related pathways. Both YST and germinoma showed significantly lower methylation at LINE1 elements compared with normal adjacent tissue while there was no difference between teratoma (mature and immature) and normal tissue. DNA methylation at imprinted loci differed significantly by tumor histology and location. Conclusion: Understanding methylation patterns may identify the developmental stage at which the GCT arose and the at-risk period when environmental exposures could be most harmful. Further, identification of relevant genetic pathways could lead to the development of new targets for therapy

Surveillance after initial surgery for pediatric and adolescent girls with stage I ovarian germ cell tumors: report from the Children's Oncology Group

PURPOSE: To determine whether overall survival (OS) can be preserved for patients with stage I pediatric malignant ovarian germ cell tumor (MOGCT) with an initial strategy of surveillance after surgical resection. PATIENTS AND METHODS: Between November 2003 and July 2011, girls age 0 to 16 years with stage I MOGCT were enrolled onto Children's Oncology Group study AGCT0132. Required histology included yolk sac, embryonal carcinoma, or choriocarcinoma. Surveillance included measurement of serum tumor markers and radiologic imaging at defined intervals. In those with residual or recurrent disease, chemotherapy with compressed PEB (cisplatin, etoposide, and bleomycin) was initiated every 3 weeks for three cycles (cisplatin 33 mg/m(2) on days 1 to 3, etoposide 167 mg/m(2) on days 1 to 3, bleomycin 15 U/m(2) on day 1). Survivor functions for event-free survival (EFS) and OS were estimated using the Kaplan-Meier method. RESULTS: Twenty-five girls (median age, 12 years) with stage I MOGCT were enrolled onto AGCT0132. Twenty-three patients had elevated alpha-fetoprotein (AFP) at diagnosis. Predominant histology was yolk sac. After a median follow-up of 42 months, 12 patients had evidence of persistent or recurrent disease (4-year EFS, 52%; 95% CI, 31% to 69%). Median time to recurrence was 2 months. All patients had elevated AFP at recurrence; six had localized disease, two had metastatic disease, and four had tumor marker elevation only. Eleven of 12 patients experiencing relapse received successful salvage chemotherapy (4-year OS, 96%; 95% CI, 74% to 99%). CONCLUSION: Fifty percent of patients with stage I pediatric MOGCT can be spared chemotherapy; treatment for those who experience recurrence preserves OS. Further study is needed to identify the factors that predict recurrence and whether this strategy can be extended successfully to older adolescents and young adults

Paediatric extracranial germ-cell tumours.

Management of paediatric extracranial germ-cell tumours carries a unique set of challenges. Germ-cell tumours are a heterogeneous group of neoplasms that present across a wide age range and vary in site, histology, and clinical behaviour. Patients with germ-cell tumours are managed by a diverse array of specialists. Thus, staging, risk stratification, and treatment approaches for germ-cell tumours have evolved disparately along several trajectories. Paediatric germ-cell tumours differ from the adolescent and adult disease in many ways, leading to complexities in applying age-appropriate, evidence-based care. Suboptimal outcomes remain for several groups of patients, including adolescents, and patients with extragonadal tumours, high tumour markers at diagnosis, or platinum-resistant disease. Survivors have significant long-term toxicities. The challenge moving forward will be to translate new insights from molecular studies and collaborative clinical data into improved patient outcomes. Future trials will be characterised by improved risk-stratification systems, biomarkers for response and toxic effects, rational reduction of therapy for low-risk patients and novel approaches for poor-risk patients, and improved international collaboration across paediatric and adult cooperative research groups.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/S1470-2045(15)00545-

Comparison of carboplatin versus cisplatin in the treatment of paediatric extracranial malignant germ cell tumours: A report of the Malignant Germ Cell International Consortium.

PURPOSE: To compare the outcomes of paediatric and adolescent extracranial malignant germ cell tumour (GCT) patients treated with either carboplatin or cisplatin on clinical trials conducted by the Children's Oncology Group (COG) and the Children's Cancer and Leukaemia Group (CCLG). METHODS: The Malignant Germ Cell International Consortium (MaGIC) has created a database of the GCT clinical trials conducted since 1983 by COG (United States, Canada and Australia), which used cisplatin-based regimens, and by CCLG (United Kingdom), which used carboplatin-based regimens. Using the parametric cure model, this study compared the overall 4-year event-free survival (EFS), stratified by age, stage, site and the a-priori defined MaGIC 'risk' groups: standard risk ((SR) 1 (EFS >80%; age 80%, age ≥ 11y) and poor risk (PR) (EFS ≤ 70%, age ≥ 11y). RESULTS: Cisplatin-based therapy was used in 620 patients; carboplatin was used in 163 patients. In the overall multivariate cure model, the two regimens did not differ significantly (cisplatin: 4-year EFS 86%; 95% confidence interval (CI) 83-89% versus carboplatin 4-year EFS 86%; 95% CI 79-90%; p = 0.87). No significant differences were noted in stratified analyses by site, stage, age and MaGIC risk groups: SR1 (p = 0.20), SR2 (p = 0.55) or PR (p = 0.72) patients. CONCLUSIONS: In these trials conducted contemporaneously, there is no significant difference in outcome observed overall, or any subset of patients, who were treated with regimens containing cisplatin versus carboplatin These results suggested sufficient equipoise to justify a randomised trial to evaluate the effectiveness of carboplatin versus cisplatin in the treatment of children, adolescents and young adults with standard risk GCT, which is currently underway

Adolescent diet and risk of breast cancer

BACKGROUND: Early life exposures, including diet, have been implicated in the etiology of breast cancer. METHODS: A nested case-control study was conducted among participants in the Nurses' Health Study who completed a 24-item questionnaire about diet during high school. There were 843 eligible cases diagnosed between onset of study (1976) and before the return of the high school diet questionnaire (1986), who were matched 10:1 with controls on the basis of age. RESULTS: Women who had, during adolescence, a higher consumption of eggs, vegetable fat and fiber had a lower risk of breast cancer, whereas risk of breast cancer was increased among women who consumed more butter. CONCLUSIONS: A possible association of elements of adolescent diet with risk of breast cancer is reported, but the findings require confirmation in prospective study