Germ Cell Tumours in Children and Young Adults
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These tumours develop from germ cells. In the developing embryo germ cells migrate to the ovaries or testicles and form the ova (egg cells) or sperm cells. Germ cell tumours occur where these cells become cancerous. These tumours typically express high levels of alphafetoprotein (AFP). Germ cell tumours are most common in children and young adults, there are different sub-types including endodermal tumours (mostly found in children), dysgerminoma, teratoma, and seminoma (young men). The most common location of these tumours are the ovaries (in females) or testicles (in males). However, they can also develop in other parts of the body such as the sacrococcygeal region, brain, abdomen and other sites - this may occur when some of the germ cells in the embryo did not migrate properly. For information on germ cell tumours of the brain see the section on brain tumours. Note: germ cell tumours in children tend to be quite different to those in adults.

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Latest Research Publications

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Information for Health Professionals / Researchers (4 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Shaikh F, Nathan PC, Hale J, et al.
Is there a role for carboplatin in the treatment of malignant germ cell tumors? A systematic review of adult and pediatric trials.
Pediatr Blood Cancer. 2013; 60(4):587-92 [PubMed]
BACKGROUND: While cisplatin is considered superior to carboplatin for the treatment of malignant germ cell tumors (MGCTs) in adults, pediatric oncology collaborative groups still remain concerned about the late effects of cisplatin in children.
METHODS: We performed a literature search to identify randomized controlled trials (RCTs) that used carboplatin for MGCTs in adults. Since no RCTs were available in children, we identified cohort studies of pediatric MGCTs treated with carboplatin. We compared the adult and pediatric studies in terms of characteristics, doses of chemotherapy, and outcomes.
RESULTS: Of 2,131 publications retrieved, five RCTs in adults (1,340 patients) and four cohort studies in children (219 patients) met criteria for inclusion. All adult RCTs evaluated carboplatin versus cisplatin regimens in men with good-prognosis metastatic MGCTs. Carboplatin regimens had a higher risk of events (RR 2.51, P < 0.001) and of deaths (RR 2.21, P < 0.001) than cisplatin regimens. Across all five RCTs, 497/654 (76%) of adults who received carboplatin remained event-free. Compared to the adult trials, three pediatric studies used carboplatin at a higher dose, frequency, and number of cycles. Across these three studies, 158/179 (88%) of children remained event-free.
CONCLUSIONS: Cisplatin is superior to carboplatin at the studied doses for the treatment of adult metastatic MGCTs. However, we observe that carboplatin is associated with good outcomes for children with MGCT when used at the higher doses. We hypothesize that a risk-adapted approach utilizing both platinum agents may achieve the optimal balance between cure and late effects.


Lin MH, Shamszadeh M, Pitukcheewanont P
Sertoli cell tumor and intratubular germ cell neoplasia located in separate gonads in an adolescent patient with complete androgen insensitivity: a case report and review of literature.
J Pediatr Endocrinol Metab. 2012; 25(5-6):547-51 [PubMed]
Complete androgen insensitivity syndrome (AIS) is an X-linked disorder of sex development. Surgical management entails timely gonadectomy given the risk of malignant transformation. Our patient presented at age 15 years with primary amenorrhea. Initial laboratory testing showed elevated testosterone, luteinizing hormone, anti-Müllerian hormone levels, and 46,XY karyotype. Imaging studies showed no uterus, ovaries, and identified two candidate gonads. She underwent bilateral gonadectomy. Pathology reports revealed Sertoli cell and intratubular germ cell tumors located in separate gonads. Our case is the first report of the youngest patient with AIS with bilateral gonadal tumors derived from different histological origins. We also review literature for reports of AIS patients with gonadal tumors. Currently, there is no consensus for the timing of gonadectomy in AIS patients. However, given the varying potential for malignant transformation of gonads in AIS patients with different phenotypes, development of a standardized treatment guideline is indicated.


Furtado SV, Thakar S, Ghosal N, Hegde AS
Atypical presentation of pediatric mixed germ cell tumors in the sellar-suprasellar region.
Neurol India. 2012 Jan-Feb; 60(1):90-3 [PubMed]
Intracranial germ cell tumors constitute a unique group of tumors, more often reported from the Asian region. Amongst them, the non-germinomatous variety occurs with a lesser frequency than the germinomatous variety. We report two children with mixed germ cell tumors with unusual clinical presentations: Central diabetes insipidus and recent-onset oculomotor palsy mimicking pituitary apoplexy. Unlike in adults, suprasellar lesions with a pituitary apoplexy-like picture in the pediatric age group may suggest a possibility of a mixed germ cell tumor.


Trabert B, Graubard BI, Erickson RL, McGlynn KA
Childhood infections, orchitis and testicular germ cell tumours: a report from the STEED study and a meta-analysis of existing data.
Br J Cancer. 2012; 106(7):1331-4 [PubMed] Free Access to Full Article
BACKGROUND: Similarities between the age-specific incidence pattern of testicular germ cell tumours (TGCTs) and the age-specific incidence pattern of cancers of viral origin prompted us to evaluate the relationship between common infections occurring during childhood or young adult life and TGCT using existing data from the US Servicemen's Testicular Tumor Environmental and Endocrine Determinants (STEED) case-control study.
METHODS: TGCT cases diagnosed between 2002 and 2005 (n=767) were matched on age, race and serum draw date to at least one control (n=929).
RESULTS: None of the infections evaluated were associated with TGCT risk. Further, a meta-analysis of mumps and mumps orchitis or orchitis infection did not support an association with TGCT (mumps pooled odds ratio (OR): 1.03, 95% confidence interval (CI): 0.89-1.20; mumps orchitis or orchitis pooled OR: 1.80, 95% CI: 0.74-4.42).
CONCLUSION: Based on our evaluation of childhood and early life infections and meta-analyses of mumps and mumps orchitis and/or orchitis, TGCT does not appear to be associated with common childhood infections.


Ye YL, Sun XZ, Zheng FF, et al.
Clinical analysis of management of pediatric testicular germ cell tumors.
Urology. 2012; 79(4):892-7 [PubMed]
OBJECTIVE: To analyze our experiences of pediatric testicular tumors and investigate the management of pediatric testicular germ cell tumors. Pediatric testicular tumors are rare and the treatment of them has not been well defined.
METHODS: Children treated for primary testicular tumors between January 1998 and July 2010 were retrospectively analyzed. For yolk sac tumor, the difference of survival rates between patients with and without retroperitoneal lymph node dissection (RPLND) was calculated.
RESULTS: Eighty-seven cases met our criteria and 78 were germ cell tumors, including 40 cases with yolk sac tumor. Patients were 3-128 months old (median 19), and 53 patients were diagnosed at younger than 2 years of age. For germ cell tumors, serum α-fetoprotein and β-human chorionic gonadotropin were elevated in 48 and 7 patients, respectively, including 38 and 2 in those with yolk sac tumor. RPLND and chemotherapy were performed in 13 and 19 patients, respectively, and surveillance was performed in 50 patients. With median follow-up of 50 months, 6 patients had recurrence, 4 patients died, and the others achieved complete remission. For stage I yolk sac tumor, the difference of survival rates between patients with and without RPLND was not significant (P = .808).
CONCLUSION: Yolk sac tumor is the most common type of pediatric testicular tumor. For stage I yolk sac tumor, radical inguinal orchiectomy is effective, salvage chemotherapy is promising, and RPLND may not be necessary.


Rescorla FJ
Pediatric germ cell tumors.
Semin Pediatr Surg. 2012; 21(1):51-60 [PubMed]
Pediatric germ cell tumors represent a diverse group of tumors that present from in utero through adolescence at many nongonadal locations, from the neck to the sacrococcygeal region. Surgical resection remains the central element of management, and accurate surgical staging is essential to properly ascertain the correct risk-based treatment. The management for all benign tumors (mature and immature teratomas) and select completely resectable malignant tumors is surgery alone. Modern-day chemotherapy is extremely effective in infants and children with unresectable and metastatic disease and these children have a very high survival rate. The use of neoadjuvant chemotherapy allows vital organ preservation and there is no role for resection of vital structures at the time of initial presentation.


Belongia M, Jogal S
Extraneural metastasis of a nongerminomatous germ cell tumor of the central nervous system in a pediatric patient with a ventriculoperitoneal shunt: a case report and review of the literature.
J Pediatr Hematol Oncol. 2012; 34(1):e12-6 [PubMed]
We describe the case of a 7-year-old white boy who presented with a mixed malignant germ cell tumor with predominant embryonal carcinoma component. The patient underwent right ventriculoperitoneal (VP) shunt placement for hydrocephalus at the time of diagnosis. He received multiagent chemotherapy followed by second-look surgery. Despite an initial response to chemotherapy, the patient had metastatic progression of disease within the craniospinal axis. He received craniospinal radiation and high-dose chemotherapy. Although, he had resolution of central nervous system (CNS) disease, follow-up off treatment revealed extra-abdominal metastases. This is a rare case to discuss abdominal metastasis of a CNS germ cell tumor in a patient with a VP shunt. The influence of VP shunt placement on treatment and management decisions of patients with CNS tumors will be discussed.


Masqué-Soler N, Szczepanowski M, Leuschner I, et al.
Absence of BRAF mutation in pediatric and adolescent germ cell tumors indicate biological differences to adult tumors.
Pediatr Blood Cancer. 2012; 59(4):732-5 [PubMed]
The V600E mutation of the BRAF gene has been reported to be associated with poor prognosis of germ cell tumors in adult patients. We analyzed the mutational status of the BRAF and KRAS gene as well as MLH1 and MSH6 expression as surrogate markers for microsatellite instability in 70 pediatric germ cell tumors. Neither BRAF and KRAS mutations nor loss of MLH1 and MSH6 expression were found. Our data provide further evidence for patient age related biological differences in germ cell tumors and demonstrate that prognostic biomarkers cannot necessarily be transferred from one age group to the other.


Poynter JN, Hooten AJ, Frazier AL, Ross JA
Associations between variants in KITLG, SPRY4, BAK1, and DMRT1 and pediatric germ cell tumors.
Genes Chromosomes Cancer. 2012; 51(3):266-71 [PubMed]
Recent genome wide association studies have identified susceptibility loci for adult testicular germ cell tumors (GCT) near KITLG, SPRY4, BAK1, and DMRT1. We evaluated variants in these four genes to determine whether these are also susceptibility loci for pediatric GCTs. DNA was isolated from 52 pediatric GCTs (ages 0-21 years) obtained from the Cooperative Human Tissue Network. Control DNA was isolated from de-identified dried blood spots from 141 white newborns. Genotyping was conducted using TaqMan assays (rs4474514) or by PCR and sequencing (rs4324715, rs210138, and rs755383). Associations between variants and GCT were evaluated using logistic regression with adjustment for sex. We also evaluated whether the associations differed by age at GCT diagnosis (0-9 years, 10-21 years), sex, and tumor location (gonadal, non-gonadal). We observed a significant association for rs210138 (BAK1) and pediatric GCT overall (odds ratio (OR) = 1.80, 95% confidence interval (CI) 1.10-2.95, P = 0.02) with non-significant associations similar in magnitude in both the pediatric (P = 0.09) and adolescent (P = 0.06) age groups. The KITLG (rs4474514) and SPRY4 (rs4324715) variants were significantly associated with GCT only in the adolescent age group (rs4474514: OR = 2.28, 95% CI 1.09-4.79, P = 0.03 and rs4324715: OR = 2.40, 95% CI 1.19-4.83, P = 0.01). Associations were mostly similar when stratified by sex. This is the first study to suggest that these loci may also be important in susceptibility to GCTs in the adolescent (KITLG, SPRY4, and BAK1) and pediatric (BAK1) age groups.


Stephansson O, Wahnström C, Pettersson A, et al.
Perinatal risk factors for childhood testicular germ-cell cancer: a Nordic population-based study.
Cancer Epidemiol. 2011; 35(6):e100-4 [PubMed]
INTRODUCTION: In contrast to research in adults, there have been limited studies on testicular germ-cell cancer among boys aged <15 years. The aim of the study was to investigate the association between perinatal characteristics and childhood testicular germ-cell cancer.
METHODS: We identified 152 patients with childhood germ-cell cancer among boys (<15 years) born in Norway, Sweden, Finland and Denmark between 1967 and 2006 using the cancer and medical birth registries. For each case we sampled 10 population controls matched on year and country of birth. We used conditional logistic regression analysis to estimate odds ratios for cancer risk.
RESULTS: There was a weak, positive association between high (≥4000 g) birth weight and childhood testicular germ-cell cancer (adjusted OR=1.25; 95% CI: 0.83-1.90) compared with normal birth weight, and a correspondingly elevated risk for low birth weight (adjusted OR=1.41; 95% CI: 0.43-4.56). For Ponderal Index (PI) there was an increased risk for low and high values compared to those in the middle category (adjusted OR=1.64; 95% CI: 1.03-2.62 and 1.67; 95% CI: 0.93-2.99), respectively. There was no association between birth length and childhood testicular germ-cell cancer. The adjusted OR for testicular cancer among first born was 1.40; 95% CI: 0.96-2.05. Greater maternal age and less maternal education appeared to increase the risk, but the estimates were not statistically significant.
CONCLUSION: We found a U-shaped association between fetal growth, measured as the PI, and childhood testicular germ-cell cancer. Our findings support the notion that abnormal fetal growth rate confers a risk in pediatric testicular cancer [corrected].


Haskins WE, Eedala S, Jadhav YL, et al.
Insights on neoplastic stem cells from gel-based proteomics of childhood germ cell tumors.
Pediatr Blood Cancer. 2012; 58(5):722-8 [PubMed] Free Access to Full Article
BACKGROUND: 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.
PROCEDURE: 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.
RESULTS: 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.
CONCLUSION: 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.


Fustino N, Rakheja D, Ateek CS, et al.
Bone morphogenetic protein signalling activity distinguishes histological subsets of paediatric germ cell tumours.
Int J Androl. 2011; 34(4 Pt 2):e218-33 [PubMed]
Germ cell tumours (GCTs) are cancers of the testis, ovary or extragonadal sites that occur in infants, children and adults. Testicular GCT is the most common cancer in young men aged 15-40 years. Abnormalities in developmental signalling pathways such as wnt/β-catenin, TGF-β/BMP and Hedgehog have been described in many childhood tumours. To date, however, the status of BMP signalling in GCTs has not been described. Herein, we examine BMP-SMAD signalling in a set of clinically-annotated paediatric GCTs. We find that BMP signalling activity is absent in undifferentiated tumours such as seminomas and dysgerminomas, but robustly present in most yolk sac tumours, a differentiated tumour type. Gene expression profiling of TGF-β/BMP pathway genes in germinomas and yolk sac tumours reveals a set of genes that distinguish the two tumour types. There is significant intertumoural heterogeneity between tumours of the same histological subclass, implying that the BMP pathway can be differentially regulated in individual tumours. Finally, through miRNA expression profiling, we identify differential regulation of a set of miRNAs predicted to target the TGF-β/BMP pathway at multiple sites. Taken together, these results suggest that the BMP signalling pathway may represent a new therapeutical target for childhood GCTs.


Mabbott DJ, Monsalves E, Spiegler BJ, et al.
Longitudinal evaluation of neurocognitive function after treatment for central nervous system germ cell tumors in childhood.
Cancer. 2011; 117(23):5402-11 [PubMed]
BACKGROUND: Central nervous system germ cell tumors (CNS GCT) are typically localized to midline structures of the brain, including the pineal and suprasellar/pituitary regions. Management of these tumors depends on underlying histology (germinoma or nongerminomatous germ cell tumor). Knowledge about neurocognitive outcome in these patients is limited. Longitudinal neurocognitive outcome in CNS GCT patients seen for neuropsychological evaluation at a single institution was explored.
METHODS: Thirty-five patients were seen for neurocognitive evaluation after diagnosis and treatment for a CNS GCT. Mean age at diagnosis was 11.66 years. Tumor location was suprasellar in 12 patients, pineal in 9, bifocal in 10, multifocal in 3, and thalamic in 1. Standardized cognitive tests of intelligence, receptive language, visual-motor ability, memory, and academic achievement were administered. Longitudinal and cross-sectional analyses were conducted.
RESULTS: Intelligence, academic functioning, and receptive vocabulary were not significantly compromised in most patients treated for CNS GCT. Working memory, information processing speed, and visual memory declined significantly over time in all patients. Patients with pineal tumors showed early and stable deficits, whereas patients with suprasellar and bifocal tumors showed more protracted declines from initial average functioning. Patients treated with ventricular versus craniospinal radiation displayed better outcome.
CONCLUSIONS: Although general cognitive abilities appeared stable and intact after treatment for most children with CNS GCT, a significant decline over time in working memory, processing speed, and visual memory was evident. Tumor location appeared to be important in understanding the trajectory of stability and decline in CNS GCT patients, as did radiation field.


Wilkening GN, Madden JR, Barton VN, et al.
Memory deficits in patients with pediatric CNS germ cell tumors.
Pediatr Blood Cancer. 2011; 57(3):486-91 [PubMed]
BACKGROUND: Germ cell tumors (GCT) of the central nervous system including germinomas and nongerminomatous germ cell tumors are rare neoplasms most commonly affecting children and adolescents. Many GCT patients seen at The Children's Hospital Denver complain of memory difficulties at the time of presentation, or demonstrate memory difficulties when assessed. Although case studies suggest that memory deficits may be associated with GCT, this is the first study to investigate memory function across a series of pediatric intracranial GCT patients.
PROCEDURE: A total of 26 GCT patients were retrospectively examined for diagnosis, imaging results, intelligence quotient, treatment variables, evidence of increased intracranial pressure at diagnosis, and memory function. Patient Full Scale IQ was measured using the Wechsler intelligence scales. Memory was evaluated with the California Verbal Learning Test.
RESULTS: The incidence of amnesia in GCT patients was 42%. GCT patients with amnesia were significantly older at diagnosis than those who did not develop amnesia. There was no association between hydrocephalus at presentation or having received radiation and the presence of memory deficits. Several cases of amnesia were not associated with involvement of classic memory structures.
CONCLUSION: The high incidence of measurable memory deficits in GCT patients suggests that amnesia may be a significant risk in this patient population. Memory assessment at diagnosis and appropriate follow-up services may prove beneficial for GCT patients.


Puumala SE, Ross JA, Wall MM, Spector LG
Pediatric germ cell tumors and parental infertility and infertility treatment: a Children's Oncology Group report.
Cancer Epidemiol. 2011; 35(5):e25-31 [PubMed] Free Access to Full Article
BACKGROUND: Few 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.
METHODS: A 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.
RESULTS: Overall, 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).
CONCLUSION: While 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.


Campbell BA, Panicker J
New onset psychosis in an adolescent during treatment of testicular germ cell tumor.
J Pediatr Hematol Oncol. 2011; 33(3):e125-6 [PubMed]
Germ cell tumor of the testis is the most common malignancy in young males between 15 and 45 years of age. Side effects of treatment are common, but psychiatric reactions have not been reported. We describe a case of a 16-year-old male patient with nonseminomatous germ cell tumor of the testis treated with orchiectomy and bleomycin, etoposide, and cisplatin chemotherapy. Treatment was complicated by the development of psychosis after first chemotherapy cycle. Etiology of psychosis was most likely multifactorial including stress related to cancer diagnosis and treatment, psychosocial and family stressors, history of traumatic brain injury, and corticosteroid medication.


Okpanyi V, Schneider DT, Zahn S, et al.
Analysis of the adenomatous polyposis coli (APC) gene in childhood and adolescent germ cell tumors.
Pediatr Blood Cancer. 2011; 56(3):384-91 [PubMed]
BACKGROUND: Aberrant Wnt signaling due to deregulation of Wnt regulators is implicated in the development and progression of numerous embryonal tumors. This study addresses the questions if activation of Wnt signaling in germ cell tumors (GCTs) arising during childhood and adolescence is associated with aberrations of the tumor suppressor adenomatous polyposis coli (APC), and whether APC aberrations might be responsible for progression from benign teratoma to malignant yolk sac tumor (YST).
PROCEDURE: Forty-eight GCTs were analyzed, including mature (n = 5) and immature (n = 7) teratomas, mixed malignant GCTs (n = 10), YSTs (n = 17) as well as dysgerminomas (n = 9). To screen APC for genetic aberrations, we conducted direct sequencing of the mutation cluster region (MCR), loss of heterozygosity analyses (LOH) and protein truncation test. Epigenetic analyses included methylation specific PCR and bisulfite genomic sequencing of the APC 1a promoter. Gene expression was determined by quantitative real-time PCR.
RESULTS: Aberrant promoter methylation was detected in YSTs, teratomas and mixed malignant GCTs, with a pronounced hypermethylation exclusively in YSTs (11/13) while dysgerminomas were not methylated (0/9). Teratomas (2/2) and YSTs (4/5) show LOH at the APC locus. However, neither mutations within the MCR nor truncated protein were detected. APC expression did not significantly vary between the different histological subgroups.
CONCLUSIONS: Methylation of APC and LOH 5q21-22 in YSTs and teratomas provide evidence for involvement of APC in the accumulation of β-catenin and activation of the WNT pathway. Our additional analyses suggest that APC is unlikely to be solely responsible for the formation and progression of childhood GCTs.


Musselman JR, Jurek AM, Johnson KJ, et al.
Maternal dietary patterns during early pregnancy and the odds of childhood germ cell tumors: A Children's Oncology Group study.
Am J Epidemiol. 2011; 173(3):282-91 [PubMed] Free Access to Full Article
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.


Poynter JN, Amatruda JF, Ross JA
Trends in incidence and survival of pediatric and adolescent patients with germ cell tumors in the United States, 1975 to 2006.
Cancer. 2010; 116(20):4882-91 [PubMed]
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: 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.


MacDonald SM, Trofimov A, Safai S, et al.
Proton radiotherapy for pediatric central nervous system germ cell tumors: early clinical outcomes.
Int J Radiat Oncol Biol Phys. 2011; 79(1):121-9 [PubMed]
PURPOSE: To report early clinical outcomes for children with central nervous system (CNS) germ cell tumors treated with protons; to compare dose distributions for intensity-modulated photon radiotherapy (IMRT), three-dimensional conformal proton radiation (3D-CPT), and intensity-modulated proton therapy with pencil beam scanning (IMPT) for whole-ventricular irradiation with and without an involved-field boost.
METHODS AND MATERIALS: All children with CNS germinoma or nongerminomatous germ cell tumor who received treatment at the Massachusetts General Hospital between 1998 and 2007 were included in this study. The IMRT, 3D-CPT, and IMPT plans were generated and compared for a representative case.
RESULTS: Twenty-two patients were treated with 3D-CPT. At a median follow-up of 28 months, there were no CNS recurrences; 1 patient had a recurrence outside the CNS. Local control, progression-free survival, and overall survival rates were 100%, 95%, and 100%, respectively. Comparable tumor volume coverage was achieved with IMRT, 3D-CPT, and IMPT. Substantial normal tissue sparing was seen with any form of proton therapy as compared with IMRT. The use of IMPT may yield additional sparing of the brain and temporal lobes.
CONCLUSIONS: Preliminary disease control with proton therapy compares favorably to the literature. Dosimetric comparisons demonstrate the advantage of proton radiation over IMRT for whole-ventricle radiation. Superior dose distributions were accomplished with fewer beam angles utilizing 3D-CPT and scanned protons. Intensity-modulated proton therapy with pencil beam scanning may improve dose distribution as compared with 3D-CPT for this treatment.


Ulbright TM, Hattab EM, Zhang S, et al.
Primitive neuroectodermal tumors in patients with testicular germ cell tumors usually resemble pediatric-type central nervous system embryonal neoplasms and lack chromosome 22 rearrangements.
Mod Pathol. 2010; 23(7):972-80 [PubMed]
Primitive neuroectodermal tumors (PNETs) are one of the most frequent types of 'non-germ cell' tumor in patients with testicular germ cell tumors and have a guarded prognosis when present in metastatic sites after cisplatin-based chemotherapy. Improved treatments, including targeted therapy, require understanding the biology of these neoplasms. We therefore analyzed the morphologic, immunohistochemical and molecular biologic features of 14 PNETs from 14 patients with concurrent or previous testicular germ cell tumors; 12 tumors were from metastatic sites and 2 were primary in the testis. Using standard light microscopic criteria for central nervous system and peripheral PNETs, we classified nine tumors as medulloepithelioma, three as medulloblastoma/supratentorial PNET, one as neuroblastic tumor with abundant neuropil and true rosettes and one as small cell embryonal tumor/PNET (Ewing sarcoma-like). Immunostains directed against INI1, CD57, S-100 protein, NeuN, WT1, neurofilament, CD99, GFAP, synaptophysin, chromogranin, AE1/AE3 cytokeratin, Fli-1 and collagen IV were performed for each case. INI1 was diffusely and strongly positive in all tumors whereas the other stains, except for cytoplasmic WT1 (which showed substantial reactivity in most tumors), were mostly focal to negative, including CD99 (eight negative, six focal) and Fli-1 (all negative). The most consistently reactive 'neuroendocrine' marker was CD57. Each case was also analyzed for chromosome 22 rearrangements using a FISH-based break-apart probe method. Only 1 tumor, classified as medulloepithelioma, was scored positive for chromosome 22 translocation (22% rearranged cells) and the remaining 13 were negative, including the one case that resembled peripheral PNET. We conclude that PNETs derived from testicular germ cell tumors mostly resemble central nervous system PNETs and generally lack the chromosome 22 translocation of peripheral PNETs. Future treatment strategies should take these findings into account.


Wang HW, Wu YH, Hsieh JY, et al.
Pediatric primary central nervous system germ cell tumors of different prognosis groups show characteristic miRNome traits and chromosome copy number variations.
BMC Genomics. 2010; 11:132 [PubMed] Free Access to Full Article
BACKGROUND: Intracranial 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.
RESULTS: We 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/beta-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.
CONCLUSIONS: Our 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.


Biswajit D, Patil CN, Sagar TG
Clinical presentation and outcome of pediatric ovarian germ cell tumor: a study of 40 patients.
J Pediatr Hematol Oncol. 2010; 32(2):e54-6 [PubMed]
BACKGROUND: Germ cell tumor is a rare malignancy accounting for 3% of all pediatric tumors. They are highly curable malignancies. The aim of this study was to evaluate the clinical presentation, management, and outcome in this subset.
METHODOLOGY: The study population included 40 patients with age less than 18 years at diagnosis. They were treated in Cancer Institute Chennai, India from 1990 to 2002. They were analyzed for the various clinical, pathologic presentations, and survival outcomes. Actuarial method was used to estimate the overall survival and relapse-free survival.
RESULTS: The mean age of the study group was 14+2.7 years with most of the patients being postpubertal. The common histologies being mixed germ cell tumor (32%) and dysgerminoma (27%). Ten percent of patients presented with ovarian torsion. Sixty-two percent of patients presented in advanced stage. Fertility preservation surgery was possible in 70% of the patients. Relapses were seen in 25% of the patients. The median duration of follow-up was 7.5 years with a 5 years disease-free survival of 72.8% and overall survival of 94.9%. Most of the patients achieved a good quality of life with normal menstrual cycles.
CONCLUSIONS: This study confirms an excellent outcome for girls with ovarian germ cell tumor, although majority of the patients presented in advanced stage. Patients with initial histology of Teratoma and Mixed germ cell tumor relapsed frequently. The mainstay of treatment being fertility preservation and cisplatin-based chemotherapy.


Johnson KJ, Poynter JN, Ross JA, et al.
Pediatric germ cell tumors and maternal vitamin supplementation: a Children's Oncology Group study.
Cancer Epidemiol Biomarkers Prev. 2009; 18(10):2661-4 [PubMed] Free Access to Full Article
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.


Grunzke M, Schreiner T, Thomison JB, et al.
Vascular compromise as a cause of sudden death in a pediatric patient with widely metastatic testicular germ cell tumor.
J Pediatr Hematol Oncol. 2009; 31(10):756-7 [PubMed]
During hospitalization for evaluation of a large testicular tumor with extensive metastatic disease, this 14-year-old boy collapsed while showering and could not be resuscitated. At autopsy, there was no evidence of thromboembolic phenomenon, a known cause of sudden death in metastatic testicular tumors and other large abdominal tumors. However, marked compression of the inferior vena cava by a large pelvicoabdominal tumor mass and findings suggestive of systemic-portal shunting were consistent with the death due to the impaired venous return via the inferior vena cava.


Johnson KJ, Ross JA, Poynter JN, et al.
Paediatric germ cell tumours and congenital abnormalities: a Children's Oncology Group study.
Br J Cancer. 2009; 101(3):518-21 [PubMed] Free Access to Full Article
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 CONCLUSIONS: Germ 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.


Elli M, Oğur G, Dağdemir A, et al.
Poland syndrome with intracranial germ cell tumor in a child.
Pediatr Hematol Oncol. 2009 Apr-May; 26(3):150-6 [PubMed]
Poland syndrome is an uncommon unilateral deformity of chest wall and upper extremity with variable manifestations. Although numerous case reports of Poland syndrome associated with malignancies have been published, intracranial germ cell tumor in Poland syndrome has not been previously reported. The authors describe a 15-year-old male patient with intracranial germ cell tumor and Poland syndrome.


Lopes LF, Macedo CR, Pontes EM, et al.
Cisplatin and etoposide in childhood germ cell tumor: brazilian pediatric oncology society protocol GCT-91.
J Clin Oncol. 2009; 27(8):1297-303 [PubMed]
PURPOSE: In 1988, we formed a consortium of Brazilian institutions to develop uniform standards for the diagnostic assessment and multidisciplinary treatment of children and adolescents with germ cell tumors. We also implemented the first childhood Brazilian germ cell tumor protocol, GCT-91, evaluating two-agent chemotherapy with cisplatin and etoposide (PE). We now report on the clinical characteristics and survival of children and adolescents with germ cell tumors treated on this protocol.
PATIENTS AND METHODS: From May 1991 to April 2000, 115 patients (106 assessable patients) were enrolled onto the Brazilian protocol with a diagnosis of germ cell tumor.
RESULTS: Patients were treated with surgery only (n = 35) and chemotherapy (n = 71). Important prognostic factors included stage (P = .025), surgical procedure at diagnosis according to resectability (P < .032), and abnormal lactate dehydrogenase value at diagnosis (P < .001).
CONCLUSION: The improvement in survival by the introduction of a standard protocol is an important achievement. This is of particular importance for smaller institutions with previous limited experience in the treatment of childhood germ cell tumors. In addition, the results of a two-agent regimen with PE were favorable (5-year overall survival rate is 83.3% for patients in the high-risk group [n = 36] who received PE v 58.8% for patients in the high-risk patients group who received PE plus ifosfamide, vinblastine, and bleomycin [n = 17; P = .017]). Thus for selected patients, complex three-agent regimens may not be necessary to achieve long-term survival, even for some patients with advanced disease.


Slaughenhoupt B, Kadlec A, Schrepferman C
Testicular microlithiasis preceding metastatic mixed germ cell tumor--first pediatric report and recommended management of testicular microlithiasis in the pediatric population.
Urology. 2009; 73(5):1029-31 [PubMed]
Testicular microlithiasis is a condition that has been associated with testis cancer in men and boys. We report the case of a 16-year-old boy who developed metastatic mixed germ cell testicular tumor in the setting of testicular microlithiasis detected by previous ultrasonography. The tumor developed in between semiannual visits and was detected by self-examination. Chest imaging revealed 2 lung lesions, and the beta-human chorionic gonadotropin level was elevated at presentation. Because of the particular nature of healthcare surveillance in the pediatric population, we recommend annual surveillance of boys with testicular microlithiasis, including physical examination, repeated instruction regarding self-examination, and ultrasonography.


Brassesco MS, Castro-Gamero AM, Valera ET, et al.
3q27 aberrations in a childhood ovary teratoma with associated malignant germ cell component.
Pediatr Blood Cancer. 2009; 52(3):398-401 [PubMed]
Cytogenetic studies of childhood ovary tumors have been poorly described. In the present article, the cytogenetic findings of an ovarian teratoma with malignant germ cell (yolk-sac) component occurring in an 8-year-old female are detailed. GTG-banding showed a karyotype of 46,XX, t(3;20)(q27;q13.3) [4]/46,XX, del3q27 [3]/46,XX [30]. Previous studies have demonstrated common sites of loss of heterozygosity at 3q27-q28 region in different types of cancer, suggesting the presence of tumor suppressor genes within this region.


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