Pediatric Germ Cell Tumors Research Articles

Pediatric germ cell tumors and parental infertility and infertility treatment: A Children's Oncology Group report

BackgroundFew risk factors have been established for childhood germ cell tumors (GCT). Parental infertility and infertility treatment may be associated with GCT development but these risk factors have not been fully investigated. MethodsA case–control study of childhood GCT was conducted through the Children's Oncology Group (COG). Cases, under the age of 15 years at diagnosis, were recruited through COG institutions from January 1993 to December 2002. Controls were obtained through random digit dialing. Information about infertility and infertility treatment along with demographic factors was collection through maternal interviews. Subgroups created by gender, age at diagnosis, and tumor location were examined separately. Statistical analysis was performed using multivariate logistic regression models. ResultsOverall, no association between GCT and infertility or its treatment was found. In subgroup analysis, females whose mothers had two or more fetal losses were found to be at increased risk for non-gonadal tumors (Odds ratio (OR)=3.32, 95% Confidence interval (CI)=1.12–9.88). Younger maternal age was associated with a lower risk of gonadal GCT in females (OR=0.52, 95% CI=0.28–0.96). There was an increased risk of all GCT and gonadal GCT in males born to older mothers (OR=2.88, 95% CI=1.13–7.37 and OR=3.70, 95% CI=1.12–12.24). ConclusionWhile no association between parental infertility or its treatment and childhood GCT was found overall, possible associations with maternal age and history of recurrent fetal loss were found in subgroups defined by gender.

High Dose Carboplatin, Etoposide, Melphalan and Autologous Hematopoietic Stem Cell Rescue with for the Treatment of Relapsed Pediatric Germ Cell Tumors

High dose chemotherapy with autologous hematopoietic stem cell transplantation (HSCT) is the treatment of choice for relapsed or refractory germ cell tumors (GCT) but few pediatric patients are included in most reports. Our objective is to describe the institutional experience with autologous HSCT for GCT.

Responses and adverse effects of carboplatin-based chemotherapy for pediatric intracranial germ cell tumors

Responses and adverse effects of carboplatin-based chemotherapy for pediatric intracranial germ cell tumors

Maternal Dietary Patterns During Early Pregnancy and the Odds of Childhood Germ Cell Tumors: A Children's Oncology Group Study

Maternal diet during pregnancy may be associated with cancer in offspring. Intake of individual foods, as well as dietary patterns, can be used when examining these relations. Here, the authors examined associations between maternal dietary intake patterns and pediatric germ cell tumors (GCTs) using principal components analysis and logistic regression. Mothers of 222 GCT cases aged less than 15 years who were diagnosed at a Children's Oncology Group institution between 1993 and 2001 and those of 336 frequency-matched controls completed a self-administered food frequency questionnaire of diet during early pregnancy. Four dietary patterns were identified: "Western," "fruits and vegetables," "protein," and "healthful." With adjustment for birth weight, parity, and vitamin use, the fruits and vegetables pattern was significantly associated with a lower odds for GCTs (odds ratio (OR) = 0.83, 95% confidence interval (CI): 0.69, 0.99; 2 sided). Upon stratification, the fruits and vegetables pattern was significantly associated with a lower odds in males (OR = 0.66, 95% CI: 0.47, 0.92) but not females (OR = 0.91, 95% CI: 0.72, 1.14). A quantitative assessment of assumed nondifferential reporting error indicated no notable deviations from unadjusted odds ratio estimates. Results of this exploratory analysis suggest that maternal prenatal dietary patterns could be considered in future studies of GCTs in offspring.

Trends in incidence and survival of pediatric and adolescent patients with germ cell tumors in the United States, 1975 to 2006

Pediatric germ cell tumors (GCTs) are rare and heterogeneous tumors with uncertain etiology. In the current study, data from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) Program were used to evaluate trends in incidence and survival of GCTs in boys and girls ages ≤19 years. To the authors' knowledge, few studies to date have evaluated trends in pediatric GCTs. Results from these analyses may provide clues to the etiology of GCTs. Frequencies, incidence rates, and 5-year relative survival rates stratified by sex were evaluated overall and by demographic subgroups based on age (birth to 9 years and 10-19 years), race (white, black, and other), and ethnicity (non-Hispanic and Hispanic) as sample size permitted. In whites, the incidence of GCTs was lower for females than males in the 10-year to 19-year age group (rate ratio [RR], 0.47; 95% confidence interval [95% CI], 0.42-0.53), whereas the rates were similar in the age group for birth to 9 years. In contrast, incidence rates were higher in black females than in black males in both age groups (RR, 2.01 [95%CI, 1.08-3.84] in those ages birth to 9 years; RR, 3.30 [95% CI, 2.13-5.28] in those ages 10-19 years). The incidence of ovarian GCT was significantly higher in Hispanic compared with non-Hispanic girls in the groups aged 10 to 19 years. Incidence rates increased during the study period in boys ages 10 to 19 years (annual percentage change [APC], 1.2; 95% CI, 0.4-2.1) and girls ages birth to 9 years (APC, 1.9; 95% CI, 0.3-2.5). The incidence of pediatric GCTs in the United States appears to be increasing only in certain subgroups, suggesting that the etiology is not completely overlapping in all age groups. Differences in incidence patterns by race and ethnicity merit further investigation.

Malignant germ cell tumors display common microRNA profiles resulting in global changes in expression of messenger RNA targets.

Despite their extensive clinical and pathologic heterogeneity, all malignant germ cell tumors (GCT) are thought to originate from primordial germ cells. However, no common biological abnormalities have been identified to date. We profiled 615 microRNAs (miRNA) in pediatric malignant GCTs, controls, and GCT cell lines (48 samples in total) and re-analyzed available miRNA expression data in adult gonadal malignant GCTs. We applied the bioinformatic algorithm Sylamer to identify miRNAs that are of biological importance by inducing global shifts in mRNA levels. The most significant differentially expressed miRNAs in malignant GCTs were all from the miR-371-373 and miR-302 clusters (adjusted P < 0.00005), which were overexpressed regardless of histologic subtype [yolk sac tumor (YST)/seminoma/embryonal carcinoma (EC)], site (gonadal/extragonadal), or patient age (pediatric/adult). Sylamer revealed that the hexamer GCACTT, complementary to the 2- to 7-nucleotide miRNA seed AAGUGC shared by six members of the miR-371-373 and miR-302 clusters, was the only sequence significantly enriched in the 3'-untranslated region of mRNAs downregulated in pediatric malignant GCTs (as a group), YSTs and ECs, and in adult YSTs (all versus nonmalignant tissue controls; P < 0.05). For the pediatric samples, downregulated genes containing the 3'-untranslated region GCACTT showed significant overrepresentation of Gene Ontology terms related to cancer-associated processes, whereas for downregulated genes lacking GCACTT, Gene Ontology terms generally represented metabolic processes only, with few genes per term (adjusted P < 0.05). We conclude that the miR-371-373 and miR-302 clusters are universally overexpressed in malignant GCTs and coordinately downregulate mRNAs involved in biologically significant pathways.

Pediatric primary central nervous system germ cell tumors of different prognosis groups show characteristic miRNome traits and chromosome copy number variations

BackgroundIntracranial pediatric germ cell tumors (GCTs) are rare and heterogeneous neoplasms and vary in histological differentiation, prognosis and clinical behavior. Germinoma and mature teratoma are GCTs that have a good prognosis, while other types of GCTs, termed nongerminomatous malignant germ cell tumors (NGMGCTs), are tumors with an intermediate or poor prognosis. The second group of tumors requires more extensive drug and irradiation treatment regimens. The mechanisms underlying the differences in incidence and prognosis of the various GCT subgroups are unclear.ResultsWe identified a distinct mRNA profile correlating with GCT histological differentiation and prognosis, and also present in this study the first miRNA profile of pediatric primary intracranial GCTs. Most of the differentially expressed miRNAs were downregulated in germinomas, but miR-142-5p and miR-146a were upregulated. Genes responsible for self-renewal (such as POU5F1 (OCT4), NANOG and KLF4) and the immune response were abundant in germinomas, while genes associated with neuron differentiation, Wnt/β-catenin pathway, invasiveness and epithelial-mesenchymal transition (including SNAI2 (SLUG) and TWIST2) were abundant in NGMGCTs. Clear transcriptome segregation based on patient survival was observed, with malignant NGMGCTs being closest to embryonic stem cells. Chromosome copy number variations (CNVs) at cytobands 4q13.3-4q28.3 and 9p11.2-9q13 correlated with GCT malignancy and clinical risk. Six genes (BANK1, CXCL9, CXCL11, DDIT4L, ELOVL6 and HERC5) within 4q13.3-4q28.3 were more abundant in germinomas.ConclusionsOur results integrate molecular profiles with clinical observations and provide insights into the underlying mechanisms causing GCT malignancy. The genes, pathways and microRNAs identified have the potential to be novel therapeutic targets.

The two most common histological subtypes of malignant germ cell tumour are distinguished by global microRNA profiles, associated with differential transcription factor expression

BackgroundWe hypothesised that differences in microRNA expression profiles contribute to the contrasting natural history and clinical outcome of the two most common types of malignant germ cell tumour (GCT), yolk sac tumours (YSTs) and germinomas.ResultsBy direct comparison, using microarray data for paediatric GCT samples and published qRT-PCR data for adult samples, we identified microRNAs significantly up-regulated in YSTs (n = 29 paediatric, 26 adult, 11 overlapping) or germinomas (n = 37 paediatric). By Taqman qRT-PCR we confirmed differential expression of 15 of 16 selected microRNAs and further validated six of these (miR-302b, miR-375, miR-200b, miR-200c, miR-122, miR-205) in an independent sample set. Interestingly, the miR-302 cluster, which is over-expressed in all malignant GCTs, showed further over-expression in YSTs versus germinomas, representing six of the top eight microRNAs over-expressed in paediatric YSTs and seven of the top 11 in adult YSTs. To explain this observation, we used mRNA expression profiles of paediatric and adult malignant GCTs to identify 10 transcription factors (TFs) consistently over-expressed in YSTs versus germinomas, followed by linear regression to confirm associations between TF and miR-302 cluster expression levels. Using the sequence motif analysis environment iMotifs, we identified predicted binding sites for four of the 10 TFs (GATA6, GATA3, TCF7L2 and MAF) in the miR-302 cluster promoter region. Finally, we showed that miR-302 family over-expression in YST is likely to be functionally significant, as mRNAs down-regulated in YSTs were enriched for 3' untranslated region sequences complementary to the common seed of miR-302a~miR-302d. Such mRNAs included mediators of key cancer-associated processes, including tumour suppressor genes, apoptosis regulators and TFs.ConclusionsDifferential microRNA expression is likely to contribute to the relatively aggressive behaviour of YSTs and may enable future improvements in clinical diagnosis and/or treatment.

Family history of cancer and malignant germ cell tumors in children: A report from the Children’s Oncology Group

Family history of testicular cancer is an established risk factor for adult testicular germ cell tumors (GCT). We evaluated the association between family history of cancer and pediatric GCT in a Children's Oncology Group case-control study that included 274 GCT cases (195 female and 79 male) diagnosed < age 15 years and 418 controls frequency matched to cases on sex and age. Family history data were collected through telephone interviews with biological mothers and fathers and unconditional logistic regression was used to evaluate associations with GCT adjusting for potential confounders. A family history of cancer with onset < age 40 years was associated with a reduced risk of GCT among female cases (Odds Ratio (OR) = 0.50, 95% Confidence Interval (CI) 0.28-0.89) and an increased risk among male cases (OR = 2.56, 95% CI 1.02-6.44). Male cases were more likely to report family history of melanoma compared with male controls (OR = 4.65, 95% CI 1.40-15.4). There was an inverse association between family history of ovarian or uterine cancers and GCT in girls (OR = 0.46, 95% CI 0.22-0.96). These sex and cancer site specific associations should be confirmed in additional studies as they may provide clues to the etiology of pediatric GCT.

Pediatric Germ Cell Tumors and Maternal Vitamin Supplementation: a Children's Oncology Group Study

Maternal vitamin supplementation has been linked to a reduced risk of several pediatric malignancies. We examined this relationship in a study of childhood germ cell tumors (GCT). Subjects included 278 GCT cases diagnosed <15 years during 1993 to 2001 at a United States or Canadian Children's Oncology Group Institution and 423 controls that were ascertained through random digit dialing matched to cases on sex, and age within 1 year. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between GCTs and maternal vitamin use at several time points during and around pregnancy. In models controlling for the child's age, sex, household income, and maternal education, any maternal vitamin use during the 6 months before conception through nursing was associated with a nonsignificant reduced risk of GCTs (OR, 0.7; 95% CI, 0.4-1.2). Inverse associations were observed for both extragonadal (OR, 0.8; 95% CI, 0.4-1.6) and gonadal (OR, 0.6; 95% CI, 0.3-1.1) tumors, and for dysgerminoma/seminoma (OR, 0.6; 95% CI, 0.2-1.3) and teratoma (OR, 0.5; 95% CI, 0.2-0.9) but not yolk sac tumors (OR, 1.1; 95% CI, 0.5-2.3). No consistent patterns were found with respect to vitamin use during the periconceptional period (6 months before pregnancy and first trimester) or first trimester specifically. In conclusion, although our study suggests that maternal vitamin supplementation may reduce the risk or pediatric GCTs in the offspring, the small study size and limitations inherent to observational studies must be considered when interpreting these results.

Paediatric germ cell tumours and congenital abnormalities: a Children's Oncology Group study

Methods:Maternally reported congenital abnormalities (CAs) were examined in a case–control study of 278 cases of paediatric germ cell tumours (GCTs) and 423 controls.Results and conclusionsGerm cell tumours were significantly associated with cryptorchidism in males (OR=10.8, 95% CI: 2.1–55.1), but not with any other specific CA in either sex.

Pediatric squamous cell carcinoma arising in an alpha‐fetoprotein‐producing mature cystic teratoma of the mandible

Teratomas, most often diagnosed in younger patients, represent the most frequently identified subtype of pediatric germ cell tumors. It is very uncommon for teratomas to present in the head and neck region and demonstrate malignant transformation. We present a case of squamous cell carcinoma arising in an alpha-fetoprotein-producing cystic teratoma of the mandible in a 2-year-old female that is, to the best of our knowledge, the first such published report. The patient was treated with surgical excision along with chemotherapy and has remained disease-free 2 years after the conclusion of therapy.

Whole Ventricular Irradiation for Pediatric Intracranial Germ Cell Tumors: A Dosimetric Study Comparing Conformal, IMRT and Helical IMRT Irradiation

Intracranial Germ Cell Tumors (GCT) account for less than 4% of pediatric brain tumors. Whole ventricular irradiation followed by a boost to the primary tumor is recommended for localized GCT. New radiation techniques may improve tumor coverage while reducing dose to the brain. A dosimetric study of the whole ventricular irradiation was conducted comparing conformal, IMRT, and helical IMRT techniques. A dosimetric study was performed on planning CT-scan of children treated by radiotherapy for CNS tumors. Ventricular CTV was defined as a 5 mm margin around T2-MRI-defined whole ventricular system. PTV included CTV plus a 2 mm margin. Organs at risk were: temporal lobes, chiasm, pituitary gland, brain stem and face. A dose of 24 Gy in 12 fractions was simulated using conformal 2 fields (plan A), conformal 5 fields (plan B), IMRT 5 fields (plan C), Helical IMRT (plan D) according to ICRU recommendations. Dosimetric plans were compared using a two-ways ANOVA statistical analysis. Six pediatric patients were included in the study. PTV coverage was achieved in all patients disregarding treatment technique. Helical IMRT significantly reduced mean dose to the temporal lobes, pituitary gland and chiasm, but not to the brainstem. Mean dose to temporal lobes was 21.5, 19.6, 17.9, 16.5 Gy for plan A, B, C, D, respectively (p < 0.0001). Mean dose to chiasm was 23.0, 23.1, 22.1, 17.8 Gy for plan A, B, C, D, respectively (p = 0.025). Mean dose to the brainstem was 19.6, 20.2, 21.9, 17.6 Gy for plan A, B, C, D, respectively (p = 0.15). Helical IMRT significantly reduced mean dose to the pituitary gland except in one patient presenting with a suprasellar GCT. Mean dose to the pituitary gland was 21.9, 22.6, 21.1, 14.3 Gy for plan A, B, C, D, respectively (p = 0.0157). Two-fields conformal irradiation significantly reduced the face volume receiving more than 2 Gy (31%, 90%, 91%, 100% for plan A, B, C, D, respectively, p < 0.0001). Helical IMRT reduces the mean dose to the temporal lobes, chiasm and pituitary, but increases low doses to normal tissues. Whole ventricular irradiation for pediatric intracranial GCT using helical IMRT may reduce the likelihood of neurological sequelae, but may increase the risk of radioinduced secondary malignancies.

Pediatric Malignant Germ Cell Tumors Show Characteristic Transcriptome Profiles

Malignant germ cell tumors (GCT) of childhood are rare and heterogeneous neoplasms thought to arise from primordial germ cells. They vary substantially in their natural history and show important clinical differences from their adult counterparts. To address the biological basis for these observations, we have undertaken a comprehensive analysis of global gene expression patterns in pediatric malignant GCTs and compared these findings with published data on adult testicular GCTs (TGCT). Our study included 27 primary tumors and assessed the principal malignant histologic types of pediatric GCT, yolk sac tumor (YST; n = 18), and seminoma (n = 9). Analysis of Affymetrix U133A GeneChip data was performed using the statistical software environment R, including gene set enrichment analysis, with cross-validation at the RNA and protein level. Unsupervised analysis showed complete separation of YSTs and seminomas by global gene expression profiles and identified a robust set of 657 discriminatory transcripts. There was no segregation of tumors of the same histology arising at different sites or at different ages within the pediatric range. In contrast, there was segregation of pediatric malignant GCTs and adult malignant TGCTs, most notably for the YSTs. The pediatric seminomas were significantly enriched for genes associated with the self-renewing pluripotent phenotype, whereas the pediatric YSTs were significantly enriched for genes associated with a differentiation and proliferation phenotype. We conclude that histologic type is the key discriminator in pediatric malignant GCTs and that the observed clinical differences between malignant GCTs of children and adults are mirrored by significant differences in global gene expression.

Genes Proximal and Distal to MYCN Are Highly Expressed in Human Neuroblastoma as Visualized by Comparative Expressed Sequence Hybridization

MYCN amplification is associated with poor prognosis in neuroblastoma disease. To improve our understanding of the influence of the MYCN amplicon and its corresponding expression, we investigated the 2p expression pattern of MYCN amplified (n = 13) and nonamplified (n = 4) cell lines and corresponding primary tumors (n = 3) using the comparative expressed sequence hybridization technique. All but one MYCN amplified cell line displayed overexpression at 2p. Expression peaks were observed frequently at 2pter and less frequently at 2p24 (MYCN locus), 2p23.3-23.2, and/or 2p23.1. Importantly, cell lines and two corresponding primary tumors displayed expression peaks at similar loci. No significant 2p24 expression level was observed for those cell lines displaying a low amplification rate (n = 3) by comparative genomic hybridization. Only the cell lines with an enhanced peak at 2p23.2-23.3 displayed coamplification of the ALK gene (2p23.2), reported to be associated with unfavorable prognosis. Finally, two of four cell lines without MYCN amplification, both derived from patients with poor outcome, also showed an expression peak at 2p23.2. These data indicate that, besides MYCN, other genes proximal and distal to MYCN are highly expressed in neuroblastoma. The prognostic significance of expression peaks at 2p23.2-23.3, independent of MYCN and ALK status, remains to be investigated.

Pediatric germ cell tumors

Pediatric germ cell tumors are a diverse group of neoplasms with variable clinical behaviors, depending upon the age and site of presentation. Most result from sporadic mutations, although environmental exposures and other genetic aberrations may play a role. Platinum-based chemotherapy has dramatically improved the event-free and overall survival outcomes of pediatric patients with malignant germ cell tumors over the past two decades. Prognosis is dependent on tumor stage and location. Patients with gonadal germ cell tumors have at least a 95% 5-year survival for early stage disease and at least a 85% 5-year survival for advanced stages. In general, extragonadal germ cell tumors carry a poorer prognosis with mediastinal location having the worst outcomes (70% 4-year survival). Current trials are focused on maintaining similar excellent outcomes while reducing morbidity by reducing the dose and duration of chemotherapy. Cytogenetic research studies have found chromosomal aberrations specific to some of these tumors that may serve as prognosticators and even direct therapy.

An Overview of Testicular Germ Cell Tumors

More than 90% of testicular neoplasms originate from germ cells. Testicular germ cell tumors (GCTs) are a heterogeneous group of neoplasms with diverse histopathology and clinical behavior. To help the readers distinguish various subtypes of GCTs, to highlight the clinical manifestations and pathologic features of these tumors, and to review several newly developed immunohistochemical markers for GCTs. Review of the pertinent literature and our experience. The etiology of GCTs is largely unknown. Cytogenetic studies suggest a different pathogenesis for each group of infantile/prepubertal GCTs, postpubertal GCTs, and spermatocytic seminoma. Unclassified intratubular germ cell neoplasia is the precursor of all GCTs, excluding spermatocytic seminoma and infantile/prepubertal GCTs. Seminoma, the most common GCT in adults, does not occur before 5 years of age. Spermatocytic seminoma, a tumor of elderly men, typically has an indolent clinical behavior, but rarely it undergoes sarcomatous transformation associated with an aggressive behavior. Embryonal carcinoma is the most common component in mixed GCTs. Eighty percent or more of embryonal carcinoma component and vascular invasion are recognized predictors of occult metastasis for clinical stage I mixed GCTs. Most patients with prepubertal yolk sac tumor, the most common pediatric GCT, have stage I disease at presentation. Most choriocarcinomas present with metastatic symptoms because of the propensity for rapid hematogenous dissemination. Teratomas in children regardless of maturity and dermoid cysts in adults are benign; in contrast, teratomas in adults have a malignant behavior. With appropriate therapy, the majority of testicular GCTs are curable.

Concordance and evaluation among IGCCCG and POG staging systems in pediatric germ cell tumors

20019 Background: The knowledge regarding treatment and prognosis of pediatric germ cell tumors has been taken from the development of these in the adult population. The object of this work was to compare the International Classification (IGCCCG) used in adults versus the POG classification used traditionally in a pediatric population. Methods: We reviewed clinical records from March 1994 through June 2003 with the diagnosis of malignant germ cell tumor of testis, retroperitoneal and mediastinum. All patients completed the treatment proposed initially with a follow up of more than 24 months. They were staged with the POG classification at diagnosis and with the International Classification for this study. Results: We obtained 61 patients with a 4 year follow up. They were all male, with germ cell tumor of testis or mediastinum. There were no retroperitoneal primary tumors. The age range was from 4 months to 188 months with an average of 48.7 months. Prognosis and treatment with the POG and the IGCCCG classifications had concordance of 0.0004 and 0.0371 respectively. Conclusions: We found limitations such as diverse chemotherapy protocols used in patients within the same risk group. Biological tumor Markers sampling play an important role in the the initial approach to allocate staging and risk based treatment protocols. It is necessary to carry out new studies with a homogeneous based population with similar diagnosis, treatment protocols and staging system to corroborate the utility and implementation of the International Classification in order to ameliorate morbidity and mortality of our pediatric patients. [Table: see text] No significant financial relationships to disclose.

Bax mutation and overexpression inversely correlate with immature phenotype and prognosis of childhood germ cell tumors

Primary childhood germ cell tumors (GCTs) represent a rare and heterogeneous group of tumors that varies in histologic differentiation, age of presentation and clinical outcome. In malignant neoplasms, apoptosis is a prognostic marker and a predictive factor of response to therapy. Therefore, the study of the expression and mutation of molecules involved in the regulation of apoptosis could be useful in order to both predict the clinical outcome and design self-tailored therapeutic approaches. We retrospectively analysed tissue samples of 54 childhood GCTs. The expression of p53 and BAX protein was assessed by immunohistochemistry (IHC). Moreover, we investigated the presence of mutations in the BAX and p53 genes SSCP-PCR and direct sequencing. IHC analysis of BAX protein expression showed that 14 out of 54 tumors (26%) had no BAX protein expression, in the remaining 40 patients (74%) the intensity of BAX was low in 20 patients (37%) and high/intermediate in 20 (37%). BAX was mutated in 6 patients. p53 was expressed in 43 patients (79.6%), was not detectable in the remaining 11 (20.4%) and mutated in only 3 patients. p53 mutational status and expression were not correlated to the overall survival (OS). On the other hand, both IHC score and mutations for BAX were correlated to sacrococcygeal primary localization. BAX mutations were inversely correlated with OS (p=0.0419) while BAX IHC intensity was directly correlated with OS (p=0.0376). The stratification for histotype showed a direct correlation between BAX IHC and OS in both immature teratoma (p=0.045) and mixed malignant GCT (p=0.010) while the correlation was lost in mature teratoma (p=0.300). These results indicate that both mutations and BAX protein levels are useful molecular biological markers for prognosis and clinical management of pediatric GCT.

Teratoma with Malignant Transformation: Experiences of the Cooperative GPOH Protocols MAKEI 83/86/89/96

The designation of a teratoma with malignant transformation (TMT) refers to the occurrence of somatic non-germ cell malignancies within a teratoma. While TMT is a rare but well recognised phenomenon in adult germ cell tumors (GCT), data on TMT in pediatric GCTs are lacking. Between 1982 and 2003, 641 patients with extracranial nontesticular pure teratoma (256 coccygeal, 246 ovarian, 139 other sites) were reported to the MAKEI protocols 83/86/89/96 by various, mainly German centres. Patients with teratoma and somatic malignancy were identified by database queries. Patients with malignant germ cell tumor components were excluded from this analysis. The clinical files were reviewed and re-evaluated centrally. Information was actualized by requisition to the participating hospitals. We identified nine patients (all female, age 0-39 years) meeting the histological criteria of TMT. Two patients had coccygeal teratomas and seven ovarian tumors. Carcinoma was the dominating malignancy (five of nine cases). Tumors with glial differentiation and embryonal tumors occurred in two cases each. Resection was performed in seven patients (including both coccygeal tumors) and adjuvant chemotherapy was administered in one of them. Two patients relapsed after resection, but both were cured with chemotherapy. Two patients suffered from advanced tumors and both were treated with primary chemotherapy. One patient was cured from the malignant component (astrocytoma), but the teratomatous components persisted. The other patient died as a result of progression of her malignant medulloepithelioma. Malignant transformation of pure teratomas constitutes a very rare entity in children and adolescents that is most commonly observed in postpubertal girls with ovarian teratoma. Compared to adult patients, similar malignant entities can be observed in association with teratoma. However, in our series, no sarcoma was diagnosed. In localised tumors, complete resection appears to be adequate, whereas chemotherapy should be considered in patients with R1- or R2-resection. Cisplatinum-based chemotherapy was effective as two of four relapsed patients survived tumor free. However, the ideal regimen has not yet been established and the known sensitivity of the histologic components to cytostatic drugs has to be considered in the choice of treatment. Further molecular biologic studies are necessary to understand the origin of these tumors.