Abstract
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.
Highlights
“Pediatric germ cell tumor” is the term used to describe malignant cancers of germline cells in patients aged 0–18 years. ese cancers may arise in the testis, the ovary, or the extragonadal sites including the sacrococcygeal area and the mediastinum
Malignant Germ Cell Tumor International Collaborative (MaGIC) investigators have produced a revised evidence-based risk stratification for pediatric and adolescent Germ cell tumors (GCTs) based on amalgamation of 25 years of clinical trial data from the US and the UK [6] that separated patients into low, standard, and poor-risk groups. is risk stratification has in turn informed the development of the clinical trial AGCT1531 recently opened by the Children’s Oncology Group, which aims to eliminate unnecessary chemotherapy in patients with Stage I disease at all sites likely cured with surgery alone who will undergo active surveillance
Mollgard et al found that primordial germ cell (PGC) migrate along nerve fibers from the midgut along the dorsal mesentery and into the gonadal ridge (GR). ese PGCs associated intimately with the peripheral Schwann cells [53]. ese data suggest that cells of the autonomic nervous system (ANS) may be responsible for secreting cytokines which PGCs recognize as migration and proliferative cues. is idea is further corroborated by studies involving the secreted neural signaling molecules PACAP and GDNF, both of which have migratory and proliferative effects on germ cells in vitro [53,54,55]. ese proteins are both secreted by the ANS and could explain the cranial, cervical, and sacrococcygeal localization of ectopic PGCs and extragonadal GCTs (EGGCTs) as these regions are thoroughly enervated by the ANS
Summary
“Pediatric germ cell tumor” is the term used to describe malignant cancers of germline cells in patients aged 0–18 years. ese cancers may arise in the testis, the ovary, or the extragonadal sites including the sacrococcygeal area and the mediastinum. While the histologic presentation and molecular biology of GCTs arising in adolescents appear similar to those in adult TGCTs, germ cell tumors in very young children have important differences (reviewed below), suggesting that they may represent a distinct disease. Treatment regimens for pediatric GCT have largely been based on clinical trial results from adult men with TGCT, who represent the largest patient population. Whether these results apply to children with gonadal or extragonadal GCT remains to be established. MaGIC investigators have produced a revised evidence-based risk stratification for pediatric and adolescent GCTs based on amalgamation of 25 years of clinical trial data from the US and the UK [6] that separated patients into low-, standard-, and poor-risk groups. E COG will be opening in the near future a trial for poor-risk patients, testing the efficacy of standard BEP chemotherapy versus accelerated BEP given every 2 weeks instead of every 3 weeks. is trial is conducted by the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP). e clinical management of pediatric GCTs was recently comprehensively reviewed [7]
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