Germ Cell Tumors In Children Research Articles

Gastric teratoma: A series of 7 cases

BackgroundGastric teratoma is a rare entity comprising less than 1% of germ cell tumors of childhood. We present a series of seven gastric teratomas with a review of literature. ObjectiveTo study the demographic profile, clinicopathological features and follow-up data of gastric teratomas. MethodsWe did a retrospective analysis of 7 cases of gastric teratomas more than 15years and studied their demographic profiles, clinicopathological features and follow-up data. ResultsWe came across 7 cases of gastric teratomas out of which 5 were mature and 2 were immature. One case of immature teratoma came back with recurrence and another one had an unusual finding of presence of renal and pulmonary tissues, which has not been reported earlier. ConclusionOurs is the second largest case series of gastric teratomas in the pediatric age group and 2 out of 7 of our cases had immature elements. We also take this opportunity to report a case of gastric teratoma with the unusual histological finding of immature renal and pulmonary tissues, which has not been described previously.

282P The prognostic value of immunohistochemical studies in diagnosis and treatment of ovarian germ cell tumors of childhood and adolescence

282P The prognostic value of immunohistochemical studies in diagnosis and treatment of ovarian germ cell tumors of childhood and adolescence

A genomic approach to study down syndrome and cancer inverse comorbidity: untangling the chromosome 21.

Down syndrome (DS), one of the most common birth defects and the most widespread genetic cause of intellectual disabilities, is caused by extra genetic material on chromosome 21 (HSA21). The increased genomic dosage of trisomy 21 is thought to be responsible for the distinct DS phenotypes, including an increased risk of developing some types of childhood leukemia and germ cell tumors. Patients with DS, however, have a strikingly lower incidence of many other solid tumors. We hypothesized that the third copy of genes located in HSA21 may have an important role on the protective effect that DS patients show against most types of solid tumors. Focusing on Copy Number Variation (CNV) array data, we have generated frequencies of deleted regions in HSA21 in four different tumor types from which DS patients have been reported to be protected. We describe three different regions of deletion pointing to a set of candidate genes that could explain the inverse comorbidity phenomenon between DS and solid tumors. In particular we found RCAN1 gene in Wilms tumors and a miRNA cluster containing miR-99A, miR-125B2 and miR-LET7C in lung, breast, and melanoma tumors as the main candidates for explaining the inverse comorbidity observed between solid tumors and DS.

Incidence of cancer in children aged 0–14 years in Taiwan, 1996–2010

Studies have found lower risk of childhood cancer among Asian children. We aim to characterize the recent incidence and incidence-trend of childhood cancer in Taiwan after the National Health Insurance program was launched in March 1995. Data were extracted from the Taiwan Cancer Registry, a population-based database established in 1979. Cases diagnosed at age 0–14 from 1996 to 2010 were analyzed and categorized according to the International Classification of Childhood Cancer, Third Edition (ICCC-3). In total, 8032 childhood cancer cases were included, with a microscopic verification rate of 93.9%. The overall age-standardized rate (ASR) of incidence adjusted to the 2000 World Standard Population is 125.0 cases/million, with a male-to-female ratio of 1.3. The top five cancer types (ICCC-3 subgroup[s]; ASR per million) are acute lymphoblastic leukemia (Ia, 30.3), acute myeloid leukemia (Ib; 9.4), non-Hodgkin lymphoma (IIb,c,e, 9.0), extracranial germ cell tumor (Xb,c; 8.3), and neuroblastoma (IVa; 7.8). The median age of diagnosis was 6 years for both genders. During the study period, the ASR of childhood cancer has been increasing at a rate of 1.2% per year (95% confidence interval, 0.6–1.7%). In contrast to Western countries, China, Japan, and Taiwan have lower incidence of childhood cancer; however, Taiwan's incidence rates of childhood germ cell tumors and hepatic tumors are higher. In conclusion, this population-based study reveals that the incidence rate of childhood cancer in Taiwan is rising consistently. The high incidence of germ cell tumors warrants further investigation.

Pediatric germ cell tumors from 1987 to 2011: incidence rates, time trends, and survival.

Malignant germ cell tumors (GCTs) are a rare and a heterogeneous group of pediatric cancers. The incidence rate has increased in some populations or subgroups. However, only a few recent publications on epidemiologic data showing the trends in incidence of pediatric GCTs are available. We analyzed the incidence rates, time trends, and survival for 1366 GCTs in children 0 to 14 years old registered in the nationwide, population-based German Childhood Cancer Registry in 1987-2011. The incidence rate of GCTs was slightly higher in girls (age-standardized rate: girls, 5.3; boys, 4.4 per million). A bimodal age distribution was seen. In children aged <1 year, the highest age-specific incidence rates were seen for girls with GCTs in the pelvis (12.7 per million) and for boys with GCTs in the testis (9.5 per million). For 10- to 14-year-old boys, the tumors occurred most often in the central nervous system (3.1 per million); for girls, the most common site was in the ovaries (4.5 per million). Only the incidence rate for ovarian GCTs increased statistically significantly. The 5- and 20-year survival probabilities for the patients diagnosed between 1987 and 2010 were 92% and 90%, respectively. Survival rates improved notably for intracranial and extragonadal GCTs from 1987 to 2006. The localization and histology of the GCTs varied between the genders and age groups. During 1987 to 2011, the incidence rate increased only for ovarian GCTs. The increase, however, may be due to changes in reporting. The survival rates were excellent.

Long-Term Outcomes of Sacrococcygeal Germ Cell Tumors in Infancy and Childhood

Purpose. The aim of this study was to evaluate long-term outcomes of sacrococcygeal germ cell tumors (SC-GCTs) over a 15-year period. Materials and Methods. A retrospective review was conducted of all pediatric patients treated for SC-GCTs at our hospital from 1998 to 2012. Results. Fifty-seven patients were treated for SC-GCTs with the most common in Altman's classification type I. Age at surgery ranged from one day to 5.6 years. Tumor resection and coccygectomy were primarily performed in about 84% of the cases. Pathology revealed mature, immature, malignant sacrococcygeal teratomas (SCTs), and endodermal sinus tumors (ESTs) in 41 (72%), 4 (77%), 6 (10.5%), and 6 (10.5%), respectively. Recurrence of discase occurred in 3 of 41 patients with mature teratomas (7.3%); 2 recurrences with mature teratomas and one recurrence with EST. Five of 6 malignant SCTs and 3 of 6 ESTs responded well to the treatment. Alpha-fetoprotein (AFP) level was elevated in both malignant teratomas and ESTs. No immediate patient death was noted in any of the 57 cases, but 4 patients with malignant tumors and distant metastasis succumbed at home within 2 years of the initial treatment. Conclusion. Benign SCTs have a significant recurrence rate of approximately 7%. Close follow-up with serial AFP level monitoring should be done for 5 years after initial tumor resection and coccygectomy. The survival rate for malignant SC-GCTs with distant metastasis was unfavorable in the present study.

Biology of childhood germ cell tumours, focussing on the significance of microRNAs.

Genomic and protein-coding transcriptomic data have suggested that germ cell tumours (GCTs) of childhood are biologically distinct from those of adulthood. Global messenger RNA profiles segregate malignant GCTs primarily by histology, but then also by age, with numerous transcripts showing age-related differential expression. Such differences are likely to account for the heterogeneous clinico-pathological behaviour of paediatric and adult malignant GCTs. In contrast, as global microRNA signatures of human tumours reflect their developmental lineage, we hypothesized that microRNA profiles would identify common biological abnormalities in all malignant GCTs owing to their presumed shared origin from primordial germ cells. MicroRNAs are short, non-protein-coding RNAs that regulate gene expression via translational repression and/or mRNA degradation. We showed that all malignant GCTs over-express the miR-371–373 and miR-302/367 clusters, regardless of patient age, histological subtype or anatomical tumour site. Furthermore, bioinformatic approaches and subsequent Gene Ontology analysis revealed that these two over-expressed microRNAs clusters co-ordinately down-regulated genes involved in biologically significant pathways in malignant GCTs. The translational potential of this finding has been demonstrated with the detection of elevated serum levels of miR-371–373 and miR-302/367 microRNAs at the time of malignant GCT diagnosis, with levels falling after treatment. The tumour-suppressor let-7 microRNA family has also been shown to be universally down-regulated in malignant GCTs, because of abundant expression of the regulatory gene LIN28. Low let-7 levels resulted in up-regulation of oncogenes including MYCN, AURKB and LIN28 itself, the latter through a direct feedback mechanism. Targeting LIN28, or restoring let-7 levels, both led to effective inhibition of this pathway. In summary, paediatric malignant GCTs show biological differences from their adult counterparts at a genomic and protein-coding transcriptome level, whereas they both display very similar microRNA expression profiles. These similarities and differences may be exploited for diagnostic and/or therapeutic purposes.

Clinical relevance of AFP, its molecular variants and HCG in hepatoblastoma and childhood germ cell tumors

Clinical relevance of AFP, its molecular variants and HCG in hepatoblastoma and childhood germ cell tumors

Incidence of Primary Central Nervous System Germ Cell Tumors in Childhood: A Regional Survey in Kumamoto Prefecture in Southern Japan

Background/Aims: Central nervous system germ cell tumors (CNS-GCTs) are relatively rare. While their incidence was thought to be higher in East Asia than the USA, recent evidence suggests the difference between Japan and the USA is not statistically significant. The aim of this study was to determine the rate of pediatric primary CNS-GCTs in Kumamoto prefecture, Japan. Methods: We surveyed 6,615 new cases of primary intracranial tumors diagnosed in Kumamoto prefecture between 1989 and 2011. Among these, 251 (3.8%) occurred in patients younger than 15 years. The age-adjusted incidence rates were calculated by the direct method using 5-year age groupings; the incidence in the total Japanese population in the year 2000 was the standard. Results: During the 23-year period, 70 cases of primary GCT were diagnosed. Of these tumors, 31 (44.3%) arose in patients aged between 0 and 14 years (22 boys, 9 girls). Their tumor location was pineal in 45.2%; the other sites were nonpineal. There were more germinomas (64.5%) than nongerminomas (35.5%) in this group. The age-adjusted annual incidence rate was 0.45 cases (boys: 0.64, girls: 0.28) per 10⁵ children. At 2.29, the ratio of CNS-GCTs was higher in these boys than girls. Our data showed higher rates than data from CBTRUS 2012 (0.18/10⁵), SEER 2008 (0.15/10⁵) and Germany (0.10/10⁵). Conclusions: Our survey showed that the incidence of primary CNS-GCTs in children was higher in Kumamoto prefecture than in the USA and other Western countries, suggesting that racial backgrounds play a role.

Ovarian Sex Cord Stromal Tumours in Children and Young Girls - A More Than Two Decade Clinicopathological Experience in a Developing Country, Pakistan

Ovarian sex-cord stromal tumours (SCST) are rare, and relatively infrequent in children. These have to be distinguished from more common germ cell tumors in children and also from benign epithelial neoplasms. The purpose of our study was to report the clinical and pathological findings in young patients with these tumours in our population. The present observational cross-sectional study included all subjects <21 years of age diagnosed with ovarian SCST, in Aga Khan University Hospital Histopathology Laboratory, Karachi, Pakistan, from January 1992 till July 2013. Of the total of 513 SCSTs presented during the study period, 39 fulfilled inclusion criteria and were assessed. The age range was 4-250 months. Most of the tumours presented at stage-1 and an abdominal mass was the most common presenting symptom, along with menstrual disturbance. The left side ovary was slightly more affected (53.5%). Of the total, 15 were juvenile granulosa cell tumours (JGCT), 11 sclerosing stromal tumours (SST), 10 of the fibrothecomas spectrum, 2 Sertoli leydig cell tumours (SLCT) and one a sex cord tumour with annular tubules (SCTAT). Detailed immunohistochemical analyses were performed in 33 cases. Recurrence/metastasis was noted in 4/21 cases with follow-up data. Ovarian sex cord stromal tumours are very rare in young age in our population, and usually present at an early stage. Most common among these are juvenile granulosa cell tumours, although surprisingly sclerosing stromal tumours were also common. Clinical symptoms due to hormone secretion in premenstrual girls and menstrual disturbance in menstruating girls are common presenting features.

Gonadal germ cell tumors in children and adolescents.

Pediatric germ cell tumors (GCT) are rare tumors: 80% are benign, 20% malignant (2-3% of all malignant pediatric tumors). The gonadal sites (ovary and testis) account for 40% of cases.Ovarian GCTs:Represent 30% of GCTs and 70% of neoplastic ovarian masses, being the most common ovarian neoplasms in children and teenagers. Benign and immature forms (teratomas) constitute about 80% of all ovarian GCTs, malignant forms represent 20% increasing during adolescence. The most common malignant entity in children is the yolk sac tumors (YST); dysgerminoma is frequent during adolescence and being bilateral in 10% of cases. Presentation is similar in malignant and benign lesions; abdominal pain (70-80%) and lower abdominal mass are common symptoms. Evaluation of alpha-fetoprotein (αFP) or beta subunit of human chorionic gonadotropin (βHCG) is essential to address the nature of the tumors: Their elevation means presence of malignancy. Surgery includes intraoperative staging procedures and requires ovariectomy or ovarosalpingectomy for malignant lesions, but may be conservative in selected benign tumors. Since malignant GCTs are very chemosensitive, primary chemotherapy is recommended in metastatic or locally advanced tumors.Testicular GCT:Represent 10% of pediatric GCT, and about 30% of malignant GCT with two age peaks: Children <3 years may experience mature teratoma and malignant GCTs, represented almost exclusively by YST, while adolescents may also show seminomas or other mixed tumors. The main clinical feature is a painless scrotal mass. Surgery represents the cornerstone of the management of testicular GCTs, with an inguinal approach and a primary high orchidectomy for malignant tumors, while a testis-sparing surgery can be considered for benign lesions. A retroperitoneal lymph node (LN) biopsy may be necessary to define the staging when the involvement of retroperitoneal LN is uncertain at imaging investigations.Conclusion:Patients with gonadal malignant GCTs fare better than those with extragonadal mediastinal germ cell tumors (MGCTs) and survival rate exceeds 90% in localized forms. Chemotherapy has significantly improved the outcome of malignant forms since the introduction of platinum based regimens. The surgical procedure has to be performed in agreement with the ongoing protocols.

Testicular sex cord stromal tumors: Analysis of patients from the MAKEI study

In children and adolescents, testicular sex cord stromal tumors (TSCSTs) are rare. There is only limited information available regarding their clinical presentation, biology, and prognosis. Between 1993 and 2009, 42 patients were prospectively reported to the cooperative MAHO and MAKEI studies on childhood germ cell tumors. Based on standardized documentation, data on epidemiology, clinical presentation, diagnostic features, histopathological differentiation, therapy, and follow-up were evaluated. During the study period, a gradual increase of the documentation of these rare tumors was observed. Palpable, indolent testicular swelling was the most common clinical finding. In three patients, retention of the testis was observed. Two patients showed sexual precocity, and one patient showed a 45X/46XY mosaic. Juvenile granulosa cell tumors (n = 16) and Sertoli cell tumor (n = 15) were the leading histopathological subtypes. The first were commonly diagnosed during the first weeks of life (median age: 6(0-162) days, the latter during infancy (median 7(0-14) months, P < 0.05). Other histological diagnoses included Leydig cell and Large Cell Calcifying Sertoli cell tumors (both n = 3) and not-otherwise-specified TSCSTs (n = 5), which were diagnosed during childhood and adolescence. All tumors were limited to the testis; there were no metastases. Treatment was surgical, only. After a median follow-up of 3.8 years, no relapse was observed. Diagnosis and therapy of testicular tumors should be planned in accordance with the recommendations of the respective childhood germ cell tumor protocols. High inguinal orchiectomy is safe and constitutes definitive therapy. Diagnostic work-up and follow-up should also consider potentially associated tumor predisposition syndromes.

Abstract 4851: MicroRNA expression in childhood germ cell tumors (GCT).

Abstract Introduction: Childhood germ cell tumors (GCTs) are a rare, heterogeneous group of malignancies classified together due to a common origin in the primordial germ cell. Studies in adults and a mouse stem cell model suggest microRNA (miRNA) expression may be involved in GCT etiology. We evaluated whether miRNA expression differed in pediatric GCTs with respect to tumor histology as well as by patient age at diagnosis and sex. Methods: MiRNA expression was measured in 44 samples from 38 individuals (38 GCT and 6 normal adjacent) using the NCounter platform (NanoString Technologies, Seattle, WA) which precisely quantifies discrete counts up to 800 miRNAs by imaging color-coded molecular barcodes. We compared miRNA expression across the main histologic subtypes of GCT (8 yolk sac tumor (YST), 8 dysgerminoma, 8 immature teratoma, and 10 mature teratoma) using NanoStride software, which analyzes raw count data from NCounter to perform differential expression analysis by employing the appropriate negative binomial distributional assumption and Benjamini-Hochberg correction (BH) for multiple testing. Results: Assessing all samples together, three miRNA species were found to significantly differ across the five categories (four tumor histologies and normal samples) (hsa-miR-371-5p, BH q-value 0.006; hsa-miR-122, BH q-value 0.03; and hsa-miR-302d, BH q-value 0.03). YSTs showed substantially higher expression of both hsa-miR-302d and hsa-miR-122 compared to all other histologies, while dysgerminomas exhibited considerably higher levels of hsa-miR-371-5. Upon pairwise analysis, YSTs differed from dysgerminomas with respect to four miRNA species (hsa-miR-375, BH q-value 0.009; hsa-miR-122, BH q-value 0.01; hsa-miR-296-5p, BH q-value 0.04; hsa-miR-1247, BH q-value 0.04) and from mature teratomas with respect to three miRNAs (hsa-miR-302d BH q-value 0.005; hsa-miR-122 BH q-value 0.008; hsa-miR-302a, BH q-value 0.01). No differences were found with respect to patient age at diagnosis or sex. When grouping all tumor samples together and comparing them to normal samples, no differences were found. Discussion: These results indicate differential expression of miRNA species by tumor histology in GCT. These could be reflective of malignancy or simply cell type as the most persistent differences were across histologic subtype not between malignant and normal samples. While differences were not found between malignant and normal samples after correction, the most significantly different species from that analysis–the miRNA 371-73 and miRNA-302 cluster–have been previously identified as differential in adult GCTs. Further study is needed to identify the RNA targets of these miRNAs and to determine their functional significance in GCTs. If confirmed in larger studies, these results suggest that miRNAs may play a significant role in childhood GCT. Citation Format: Jessica R.B. Musselman, Julie A. Ross, Weihua Guan, Jenny N. Poynter. MicroRNA expression in childhood germ cell tumors (GCT). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4851. doi:10.1158/1538-7445.AM2013-4851

Malignant Sacrococcygeal Germ Cell Tumors in Children: A 30-year Experience from a Single Institution

Our aim was to analyze treatment results and survival characteristics of our patients with malignant sacrococcygeal germ cell tumors. Patient files of children with malignant sacrococcygeal germ cell tumors, treated at our institution between 1979 and 2009, were searched. Patient characteristics, histopathological subtypes, extension of disease, alpha-fetoprotein (AFP) level at the time of diagnosis and relapse, extent of surgical resection, chemotherapy protocols, details of radiotherapy and survival characteristics were recorded. A total of 58 patients (M/F = 20/38) with malignant sacrococcygeal germ cell tumor was included in analysis. With a mean follow-up of 156 months (range, 26 days to 288.8 months) overall and event-free survival rates of the 58 patients were 50.9% and 43.8%, respectively. AFP status of the patients (37% in patients with <10,000 ng/ml, 68.9% in patients with ≥ 10,000 ng/ml), type of resection (total vs others), coccygeal resection, chemotherapy protocol (PEB vs others) and number of chemotherapy courses had an impact on event-free survival in univariate analysis. In multivariate analysis, AFP status had the greatest effect on prognosis. Our treatment results are worse than those reported in the literature. Elevated AFP level at the time of diagnosis had a beneficial effect on prognosis, but year of diagnosis, tumor stage, presence of metastasis, tumor size and histopathological subtype had no impact on survival in patients with malignant sacrococcygeal germ cell tumors.

Fever of unknown origin: A case of post obstructive pneumonia complicating mature teratoma

Mediastinal teratomas are rare germ cell tumors in children accounting for only 4.3% of all germ cell tumours. Here, we describe a three year old child who was misdiagnosed as a case of pulmonary tuberculosis at periphery despite of his chest X ray showing large homogenous opacification of left hemithorax with areas of calcifications and subsequently diagnosed as a case of benign mature teratoma with post obstructive pneumonia. Our case highlights the need for careful evaluation of chest X-ray (CXR) by the treating physicians, especially when CXR had a large homogenous opacity with shifting of mediastinum and presence of a few calcified shadows, which may clinch a rare diagnosis of an uncommon disorder.

Mediastinal Germ Cell Tumors in Childhood

Background: Mediastinal germ cell tumors (GCTs) are rare and usually located in anterior mediastinum. We aimed to review clinical and pathological characteristics of these tumors. Procedure: Between 1973 and 2011, 24 children with mediastinal GCTs were diagnosed. Hospital files were reviewed for presenting complaints, clinical, radiological and other laboratory data, surgical practices, treatments, and outcomes. Results: Median age was 4.5 years (0.2–16) (male/female: 10/14). Most common initial complaints were dyspnea, cough, anorexia/fatigue, fever, and chest pain. Primary tumors were located in anterior mediastinum (n = 22), posterior mediastinum (n = 1), and sternum (n = 1). Thirteen of 24 cases had mature teratomas (54.2%); four (16.7%) endodermal sinus tumor (EST); four (16.7%) immature teratomas; and one (4.2%) each of embryonal carcinoma, teratocarcinoma, and malignant teratoma. Mature teratomas underwent only surgical resection and were under follow-up without disease. Four cases with ESTs received chemotherapy and radiotherapy (n = 3), three underwent surgical resections: three died, one was followed for 284 months in remission. All but one immature teratomas were treated with surgery and all were under follow-up without disease. Two patients with embryonal carcinoma and malignant teratoma didn't undergo surgery; both received chemotherapy and radiotherapy but died with disease. The patient with teratocarcinoma was treated with surgery and chemotherapy but died with disease. Conclusions: No adjuvant therapy is needed for mature teratomas. Immature teratomas must be under close follow-up for recurrences. Prognosis for mediastinal malignant GCTs was poor. These cases need intensive chemotherapies and effective local control measures as surgery –/+ radiotherapy to ensure long-term survival.

Bleomycin-associated lung toxicity in childhood cancer survivors.

9591 Background: Bleomycin has been established as a pulmonary toxin, but the risk for toxicity in survivors of childhood cancer is poorly characterized. Methods: We conducted a cross-sectional study of lung function in survivors of childhood Hodgkin lymphoma and germ cell tumor treated with bleomycin at our institution between 1997 and 2010. We assessed their most recent post-therapy pulmonary function test (PFT). Spirometry and lung volumes were categorized as normal, restrictive, obstructive or mixed. Diffusing capacity of carbon monoxide (DLCO) was categorized as normal or abnormal. Results: 195 patients were treated with bleomycin. Ten died of non-pulmonary causes. Of 185 survivors, 143 (77%) had complete data available for analysis. Median cumulative bleomycin dose was 60U/m2 (IQR 30-60). Three patients (2%) had a history of acute bleomycin toxicity. PFTs were performed a median of 2.3 years (IQR 1.4-4.9) from completion of therapy. Spirometry was abnormal in 58 patients (41%); of whom 5 (9%) had respiratory symptoms. 42 (70%) had obstructive, 11 (18%) restrictive and 5 (9%) mixed ventilatory defects. Abnormalities were mild in 53 (91%), moderate in 3 (5%) and severe in 2 (4%). DLCO was abnormal in 27 patients, 26 (96%) of whom had mildly reduced DLCO and were asymptomatic. Univariate analysis did not demonstrate a significant association between gender, smoking, lung metastases, lung radiation, chemotherapy regimen, or autologous transplant and abnormal lung function. Disease relapse was associated with abnormal lung function (p=0.01). Smoking (p=0.04) and relapse (p=0.03) were associated with abnormal DLCO. The odds ratio of developing abnormal spirometry for each 1unit/m2 increase in bleomycin was 1.01 (95% CI 1.00-1.02, p=0.07). Conclusions: Childhood cancer survivors treated with bleomycin frequently have evidence of asymptomatic abnormalities on PFT. The current recommendation for pulmonary function testing in childhood cancer survivors appears justified.

Atypical extragonadal germ cell tumors

Aim:To review the experience with the diagnosis and management of extragonadal germ cell tumors (GCT) with a subset analysis of those with atypical features.Materials and Methods:A retrospective chart review of patients of extragonadal germ cell tumors between 2000 and 2010 was carried out.Results:Fifteen children aged 7 days to 15 years (median, 1.5 years) were included. Three had an antenatal diagnosis (one sacrococcygeal, one retrobulbar, one retroperitoneal tumor) and were operated in the neonatal period. The locations were distributed between the retrobulbar area (1), anterior neck-thyroid gland (1), mediastinum (4), abdominothoracic extending through the esophageal hiatus (1), retroperitoneal (4) and sacrococcygeal (4). On histological examination, five harbored immature elements while two were malignant; the latter children received postexcision adjuvant chemotherapy. There was no mortality. At a median follow-up of 4.5 years (6 months to 8 years), 14/15 have had an event-free survival. One immature mediastinal teratoma that recurred locally 7.5 years after the initial operation was excised and adjuvant chemotherapy instituted.Conclusions:Extragonadal GCTs in children are uncommon and occasionally present with atypical clinical, radiological and histological features resulting in diagnostic and therapeutic dilemmas.

Insights on neoplastic stem cells from gel‐based proteomics of childhood germ cell tumors

Childhood germ cell tumors (cGCTs), believed to arise from transformed primordial germ cells by an unknown mechanism, provide a unique model system for investigating cell signaling, pluripotency, and the microenvironment of neoplastic stem cells (NSCs) in vivo. This is the first report of proteomics of cGCTs. Four dysgerminomas (DYSs) and four childhood endodermal sinus tumors (cESTs), resembling self-renewing and differentiating NSCs, respectively, were selected. Proteomic studies were performed by 2-DE, SDS-PAGE, and cLC/MS/MS with protein database searching. 2-DE: 9 of 941 spots were differentially regulated with greater than a twofold change in spot volume for at least three of four gels in each group. Two of nine spots had P values for the t-test analysis of comparisons less than 0.001, while the remaining spots had P values from 0.013 to 0.191. Top-ranked proteins were identified in nine of nine spots with 4.0-38% sequence coverage. APOA1, CRK, and PDIA3 were up-regulated in cESTs. TFG, TYMP, VCP, RBBP, FKBP4, and BiP were up-regulated in DYSs. SDS-PAGE: Up-regulation of NF45 and FKBP4 was observed in four of four cESTs and DYSs, respectively. The fold-changes observed correspond with characteristic genetic changes. Differential regulation of FKBP4 and NF45, combined with previous research on immunosuppressant binding, suggests that glucocorticoid receptor signaling merits further investigation in cGCTs and NSCs.

Methylator phenotype of malignant germ cell tumours in children identifies strong candidates for chemotherapy resistance

Background:Yolk sac tumours (YSTs) and germinomas are the two major pure histological subtypes of germ cell tumours. To date, the role of DNA methylation in the aetiology of this class of tumour has only been analysed in adult testicular forms and with respect to only a few genes.Methods:A bank of paediatric tumours was analysed for global methylation of LINE-1 repeat elements and global methylation of regulatory elements using GoldenGate methylation arrays.Results:Both germinomas and YSTs exhibited significant global hypomethylation of LINE-1 elements. However, in germinomas, methylation of gene regulatory regions differed little from control samples, whereas YSTs exhibited increased methylation at a large proportion of the loci tested, showing a ‘methylator’ phenotype, including silencing of genes associated with Caspase-8-dependent apoptosis. Furthermore, we found that the methylator phenotype of YSTs was coincident with higher levels of expression of the DNA methyltransferase, DNA (cytosine-5)-methyltransferase 3B, suggesting a mechanism underlying the phenotype.Conclusion:Epigenetic silencing of a large number of potential tumour suppressor genes in YSTs might explain why they exhibit a more aggressive natural history than germinomas and silencing of genes associated with Caspase-8-dependent cell death might explain the relative resistance of YSTs to conventional therapy.