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1.  Pediatric germ cell tumors and parental infertility and infertility treatment: a Children’s Oncology Group Report 
Cancer epidemiology  2011;35(5):e25-e31.
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.
doi:10.1016/j.canep.2011.01.009
PMCID: PMC3142313  PMID: 21474408
Germ cell tumor; infertility; pediatrics; epidemiology
2.  A Mini-Review of Familial Ovarian Germ Cell Tumors: An Additional Manifestation of the Familial Testicular Germ Cell Tumor Syndrome 
Cancer epidemiology  2009;33(1):31-36.
Introduction
While testicular germ cell tumors (TGCTs) are the most common malignancy in young men, germ cell tumors in women are uncommon. Familial clustering, epidemiologic evidence of increased risk with family or personal history of TGCT, and associations with genitourinary tract anomalies suggest an underlying genetic predisposition to TGCT, but traditional linkage studies have yet to identify a highlypenetrant TGCT cancer susceptibility gene. In this paper, we investigate the familial occurrence of testicular and ovarian germ cell tumors.
Methods
We report a family in which a TGCT and an ovarian germ cell tumor (OGCT) occurred in two siblings, summarize the existing literature on familial occurrences of OGCT, either alone or in combination with extragonadal or TGCTs, and compare the incidence of familial and sporadic testicular and ovarian GCTs. Sporadic GCT data were obtained from the US Surveillance Epidemiology and End Results (SEER) registry.
Results
We identified 16 reports of OGCT occurring in conjunction with either ovarian, testicular or extragonadal GCT. In these familial cases, the mean age at onset of female dysgerminoma was younger than that noted in the general population (age 17 vs age 24, p=0.01). In SEER, the incidence of TGCT was 15 times higher than that of OGCT. Histologic distributions in males and females showed distinctly different patterns.
Discussion
Although the incidence of OGCTs in the general population is quite low, its occurrence in multiple members of the same family and in families with TGCT suggests that a gene conferring susceptibility to GCTs may exist in some families.
doi:10.1016/j.canep.2009.04.015
PMCID: PMC2735217  PMID: 19679044
ovarian germ cell tumor; familial; epidemiology; testicular germ cell tumor; genetic predisposition; SEER
3.  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 (GCTs). Subjects included 278 GCT cases diagnosed <15 years during 1993-2001 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 one year. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% Confidence Intervals (CIs) 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 prior to conception through nursing was associated with a non-significant reduced risk of GCTs (OR=0.7; 95% CI 0.0.4-1.2). 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, while 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.
doi:10.1158/1055-9965.EPI-09-0462
PMCID: PMC2759848  PMID: 19755653
germ cell tumors; pediatrics; prenatal vitamins; folic acid; risk factors
4.  Predictors of viable germ cell tumor in postchemotherapeutic residual retroperitoneal masses 
Urology Annals  2014;6(1):27-30.
Objective:
The aim of this study was to identify predictors of viable germ cell tumor (GCT) in postchemotherapeutic residual retroperitoneal masses.
Materials and Methods:
The pertinent clinical and pathologic data of 16 male patients who underwent postchemotherapeutic retroperitoneal lymph node dissection (PC-RPLND) at King Faisal Specialist Hospital and Research Centre between 1994 and 2005 were reviewed retrospectively. It was found that all patients received cisplatin-based chemotherapy for advanced testicular GCT.
Results:
Out of the 16 male patients, 2 (13%), 8 (50%), and 6 (37%) had viable GCT, fibrosis, and teratoma, respectively. Ten (10) of the patients with prechemotherapeutic S1 tumor markers did not have viable GCT, and two of the six patients who had prechemotherapeutic S2 tumor markers have viable GCT. All tumor marker levels normalized after chemotherapy even in patients with viable GCT. Four patients had vascular invasion without viable GCT. Furthermore, four patients had more than 60% embryonal elements in the original pathology, but only 1 had viable GCT at PC-RPLND. Four of the five patients with immature teratoma had teratoma at PC-RPLND but no viable GCT; however, out of the four patients with mature teratoma, one had viable GCT and two had teratoma at PC-RPLND. Of the two patients with viable GCT, one had 100% embryonal cancer in the original pathology, prechemotherapeutic S2 tumor markers, history of orchiopexy, and no vascular invasion; the other patient had yolk sac tumor with 25% embryonal elements and 40% teratoma in the original pathology, and prechemotherapeutic S2 tumor markers.
Conclusion:
None of the clinical or pathological parameters showed a strong correlation with the presence of viable GCT in PC-RPLND. However, patients with ≥S2 may be at higher risk to have viable GCT. Further studies are needed to clarify this.
doi:10.4103/0974-7796.127017
PMCID: PMC3963339  PMID: 24669118
Chemotherapy; germ cell tumor; predictor; retroperitoneal lymph node dissection
5.  Maternal Dietary Patterns During Early Pregnancy and the Odds of Childhood Germ Cell Tumors: A Children's Oncology Group Study 
American Journal of Epidemiology  2010;173(3):282-291.
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.
doi:10.1093/aje/kwq365
PMCID: PMC3105268  PMID: 21098631
eating; factor analysis; mental recall; neoplasms, germ cell and embryonal; prenatal nutritional physiological phenomena
6.  Sequential bilateral testicular tumours presenting with intervals of 20 years and more 
BMC Urology  2013;13:71.
Background
About 3 – 5% of all patients with testicular germ cell tumour (GCT) develop a contralateral cancer, the majority of which arise within 10–15 years. Little is known about the risk of second GCTs after more than two decades. Here we present 3 cases with very late presenting contralateral GCT and provide a summary of similar cases reported previously.
Case presentations
(1) This white Caucasian man underwent right-sided orchiectomy for a nonseminomatous GCT at the age of 22 years. Additional treatment consisted of retroperitoneal lymph node dissection (RPLND) and chemotherapy with 4 cycles of vinblastin / bleomycin. 36 years later, contralateral seminoma clinical stage 1 developed. Cure was achieved by orchiectomy. Histologically, testicular intraepithelial neoplasia (TIN; intratubular germ cell neoplasia) was detected in the tumour-surrounding tissue.
(2) This white Caucasian male had right-sided orchiectomy for nonseminomatous GCT at the age of 29 years. Pathological stage 1 was confirmed by RPLND. 25 years later, he received left sided orchiectomy for seminoma stage 1. Histologically, TIN was found in the tissue adjacent to seminoma. Two brothers had testicular GCT, too, one with bilateral GCT. (3) This 21 year old white Caucasian man underwent left-sided orchiectomy for nonseminomatous GCT. Pathological stage 1 was confirmed by RPLND. 21 years later, he received organ-preserving excision of a right-sided seminoma, followed by BEP chemotherapy for stage 3 disease. Histologically, TIN was found in the surrounding testicular tissue.
22 cases of bilateral GCT with intervals of 20 or more years have previously been reported, thereof three with intervals of more than 30 years, the longest interval being 40 years.
Conclusion
Apart from increased risks of cardiovascular diseases and non-testicular malignancies, patients with GCT face the specific probability of a second GCT in the long run. This risk persists life-long and is not eliminated by chemotherapy. Contralateral testicular biopsy can identify patients at risk by revealing precursor cells of GCT though false-negative biopsies may occur sporadically. However, in view of the multi-facetted late hazards of GCT patients, this minor surgical procedure might somewhat simplify the long-time care of these patients.
doi:10.1186/1471-2490-13-71
PMCID: PMC4028980  PMID: 24321309
Testicular germ cell neoplasms; Bilateral tumours; Testicular biopsy; Seminoma; Familial germ cell tumours
7.  Trends in Incidence and Survival of Pediatric and Adolescent Germ Cell Tumors in the United States, 1975-2006 
Cancer  2010;116(20):4882-4891.
Background
Pediatric germ cell tumors (GCTs) are rare and heterogeneous tumors with uncertain etiology. We used data from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) Program to evaluate trends in incidence and survival of GCTs in boys and girls ≤ 19 years of age. Few studies have evaluated trends in pediatric GCTs. Results from these analyses may provide clues to the etiology of GCTs.
Methods
Frequencies, incidence rates and five-year relative survival rates stratified by sex were evaluated overall and for demographic subgroups based on age (0-9 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 10-19 year age group (RR=0.47, 95% CI 0.42—0.53) while the rates were similar in the 0-9 year age group. 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 0-9 year olds; RR=3.30, 95% CI 2.13—5.28 in 10-19 year olds). The incidence of ovarian GCT was significantly higher in Hispanic than non-Hispanic girls in the 10—19 year age group. Incidence rates increased during the study period in boys ages 10-19 (APC 1.2, 95% CI 0.4—2.1) and girls ages 0-9 (APC 1.9, 95% CI 0.3-2.5).
Conclusions
The incidence of pediatric GCTs in the United States is 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.
doi:10.1002/cncr.25454
PMCID: PMC3931133  PMID: 20597129
pediatric cancer; germ cell tumors; SEER; incidence
8.  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.
doi:10.4103/0971-9261.141995
PMCID: PMC4204242  PMID: 25336799
Children; germ cell tumors; gonadal
9.  Tallness is associated with risk of testicular cancer: evidence for the nutrition hypothesis 
British Journal of Cancer  2008;99(9):1517-1521.
The pathogenesis of testicular germ cell tumours (GCTs) is potentially influenced by high-energy nutrition during infancy. As adult height is a proxy for childhood nutrition, we investigated the role of nutrition in GCT pathogenesis by comparing stature of patients with healthy men. In a matched case–control study, 6415 patients with GCT were compared with healthy army conscripts (1:6 matching modus) with regard to height (cm) and body mass index (BMI; kg/m2). Statistical analysis involved tabulation of descriptive height measures and BMI. Conditional logistic regression models were used to quantify the association of GCT with height, with odds ratios (OR) adjusted for BMI. The literature was searched for studies on stature in GCT patients. Body size is significantly associated with risk of GCT, very tall men (>195 cm) having a GCT risk of OR=3.35 (95% confidence intervals (CI): 2.88–3.90; adjusted). Short stature is protective (OR=0.798; 95% CI: 0.68–0.93). Both histologic subgroups are associated with tallness. Of 16 previous reports, 7 were confirmative, 5 had null and 4 equivocal results. The association of stature with GCT risk accords with the nutrition hypothesis of GCT. This study expands the current view of GCT tumorigenesis by suggesting that high-calorie intake in childhood promotes GCT precursors originating in utero.
doi:10.1038/sj.bjc.6604695
PMCID: PMC2579680  PMID: 18827809
testicular cancer; body size; childhood nutrition; seminoma; non-seminoma; BMI
10.  Delayed Recognition of Disorders of Sex Development (DSD): A Missed Opportunity for Early Diagnosis of Malignant Germ Cell Tumors 
Disorders of sex development (DSD) are defined as a congenital condition in which development of chromosomal, gonadal or anatomical sex is atypical. DSD patients with gonadal dysgenesis or hypovirilization, containing part of the Y chromosome (GBY), have an increased risk for malignant type II germ cell tumors (GCTs: seminomas and nonseminomas). DSD may be diagnosed in newborns (e.g., ambiguous genitalia), or later in life, even at or after puberty. Here we describe three independent male patients with a GCT; two were retrospectively recognized as DSD, based on the histological identification of both carcinoma in situ and gonadoblastoma in a single gonad as the cancer precursor. Hypospadias and cryptorchidism in their history are consistent with this conclusion. The power of recognition of these parameters is demonstrated by the third patient, in which the precursor lesion was diagnosed before progression to invasiveness. Early recognition based on these clinical parameters could have prevented development of (metastatic) cancer, to be treated by systemic therapy. All three patients showed a normal male 46,XY karyotype, without obvious genetic rearrangements by high-resolution whole-genome copy number analysis. These cases demonstrate overlap between DSD and the so-called testicular dysgenesis syndrome (TDS), of significant relevance for identification of individuals at increased risk for development of a malignant GCT.
doi:10.1155/2012/671209
PMCID: PMC3272341  PMID: 22315593
11.  Testicular Germ Cell Tumors with Sarcomatous Components: An Analysis of 33 Cases 
The American journal of surgical pathology  2009;33(8):10.1097/PAS.0b013e3181adb9d7.
The development of sarcomatous component (SC) in testicular germ cell tumor (GCT) is an uncommon phenomenon. We searched our surgical pathology files from 1985 to 2007 and identified 33 cases of testicular GCTs with SC. The average age of patients was 31 years. All patients underwent radical orchiectomy, which demonstrated a GCT in all patients except for 3 patients who had received neoadjuvant chemotherapy. All testicular GCTs contained a teratomatous component. The GCTs were pure teratomas in 3 cases, and were mixed GCTs in the other cases. The SC was observed in primary testicular tumor (n = 19), in metastasis (n = 11), or in both primary testicular tumor and metastasis (n=3). The average percentage of the SC in the primary testicular GCT was 32% (range, 5% to 99%). The most common histologic type of SC was rhabdomyosarcoma (n = 24), followed by high-grade unclassified sarcoma (n = 5), rhabdomyosarcoma admixed with high-grade unclassified sarcoma (n = 2), angiosarcoma (n = 1), and low-grade myxoid sarcoma (n = 1). Clinical follow-up information was available for 27 patients. Of the 13 patients whose SC was limited to the testicular GCT, 2 died of GCT not otherwise specified (NOS) at 37 and 68 months, respectively; and 11 patients were free of disease at a mean of 46 months. Of the 14 patients with a SC in the metastasis, 7 patients died of GCT NOS at a mean of 95 months, and 7 patients were free of disease at a mean of 104 months. These results suggest that patients with a SC confined to the primary testicular GCT may not have a higher risk of mortality than those at a comparable stage without a SC. However, patients with a SC in the metastasis have an increased risk of mortality.
doi:10.1097/PAS.0b013e3181adb9d7
PMCID: PMC3812063  PMID: 19561445
testicular germ cell tumor; sarcomatous component; rhabdomyosarcoma
12.  Gonadal and extragonadal germ cell tumors in the United States, 1973–2007 
Germ cell tumors (GCTs) most often arise in the gonads but some develop extragonadally. The aim of this study was to examine sex- and race-specific trends in incidence and survival of gonadal (GGCTs) and extragonadal GCTs (EGCTs) in the US from 1973 to 2007. We also examined the topographic distribution of EGCTs by race and sex.
We estimated age-specific and age-standardized incidence rates and 5-year relative survival rates (RSR) of GCTs using the Surveillance, Epidemiology, and End Results (SEER) Program (SEER 9 registries). GCTs and their topographic sites were identified using ICD-O morphology and topography codes.
Of 21,170 GCTs among males, 5.7% were extragonadal (whites 5.5%; blacks 16.3%). Of 2,093 GCTs among females, 39.3% were extragonadal (whites, 36.9%; blacks 51.0%). The incidence of GGCT was much higher among white (56.3/1,000,000) than black males (10.0/1,000,000) while there was no difference in incidence between white and black females (3.2/1,000,000). The rates of EGCT among men and women of both races were similar (range:1.9 – 3.4/1,000,000). The most frequent extragonadal sites were mediastinum among males and placenta among females. The 5-year RSR of testicular GCT was higher among whites (97%) than blacks (90%), as was the 5-year RSR of ovarian GCT (whites, 92%; blacks 85%). In general, the 5-year RSRs of EGCTs were lower than the 5-year RSRs of GGCTs.
The different incidence trends of GGCTs and EGCTs and distinct age-specific incidence patterns by anatomic site of EGCTs suggests that GGCTs and EGCTs may have different etiologies.
doi:10.1111/j.1365-2605.2011.01245.x
PMCID: PMC3631107  PMID: 22320869
testicular neoplasms; ovarian neoplasms; incidence; time trends; germ cell tumors; extragonadal germ cell tumors
13.  Descriptive epidemiology of central nervous system germ cell tumors: nonpineal analysis† 
Neuro-Oncology  2009;12(3):257-264.
Central nervous system (CNS) germ cell tumors (GCT) have not been epidemiologically well described. Our study describes 2 population-based series of nonpineal CNS GCT. Data on all primary (malignant and nonmalignant) CNS (ICD-O-3 sites: C70.0–C72.9, C75.1–C75.3) GCT diagnosed between 2000 and 2004 from the Central Brain Tumor Registry of the United States (CBTRUS) and on all malignant GCT diagnosed between 1992 and 2005 from the Surveillance, Epidemiology, and End Results (SEER) were analyzed. Of 234 nonpineal GCT in CBTRUS, the most common site was brain, NOS (31.6%). Males had a greater frequency (59.7%) than females (40.3%). However, by age group, the male-to-female incidence rate ratio (IRR) differed: children (0–14 years) had an IRR of 1.1, young adults (15–29 years) an IRR of 2.3, and adults (aged 30+) an IRR of 1.0. For children and young adults, most tumors were malignant (86.8% and 89.0%, respectively), whereas for adults, more than half were nonmalignant (56.8%). Germinoma was the most frequent diagnosis (61.5%). In SEER, the frequency of malignant GCT in the CNS (2.5%) was greater than that in the mediastinum (2.1%). Of 408 malignant CNS GCT, 216 (52.9%) were nonpineal. The male-to-female IRR was 1.5. Overall relative survival for nonpineal CNS malignant GCT was 85.3% at 2 years, 77.3% at 5 years, and 67.6% at 10 years. Previous studies of GCT that have not stratified by site have suggested greater gender disparity. Nonpineal CNS GCT show no significant gender preference, yet have outcomes similar to pineal GCT.
doi:10.1093/neuonc/nop029
PMCID: PMC2940596  PMID: 20167813
brain tumor; epidemiology; germ cell tumors; germinoma; teratoma
14.  The risk of thrombo-embolic events is increased in patients with germ-cell tumours and can be predicted by serum lactate dehydrogenase and body surface area 
British Journal of Cancer  2005;93(8):909-914.
The aim of this study was to evaluate the risk of thrombo-embolic events (TEE) in patients with germ-cell tumours (GCT) who receive cisplatin-based chemotherapy, to compare this risk to that of a matched control group of non-GCT cancer patients, and to identify risk factors of TEE. The rate of TEE during the 6 months following the initiation of chemotherapy was assessed in 100 consecutive patients with GCT and in 100 controls with various neoplasms who were matched on sex and age, and who received first-line cisplatin-based chemotherapy during the same period of time at Institut Gustave Roussy, Villejuif, France. Data were subsequently tested on a validation group of 77 GCT patients treated in Lyon, France. A total of 19 patients (19%) (95% confidence interval (CI): 13–28) and six patients (6%) (95% CI: 3–13) had a TEE in the GCT group and the non-GCT control group, respectively (relative risk (RR): 3.4; P<0.01). Three patients from the GCT group died of pulmonary embolism. In multivariate analysis, two factors had independent predictive value for TEE: a high body surface area (>1.9 m2) (RR: 5 (1.8–13.9)) and an elevated serum lactate dehydrogenase (LDH) (RR: 6.4 (2.3–18.2)). Patients with no risk factor (n=26) and those with at least one risk factor (n=71) had a probability of having a TEE of 4% (95% CI: 1–19) and 26% (95% CI: 17–37), respectively. In the GCT validation set, 10 (13%) patients had a TEE; patients with no risk factor and those with at least one risk factor had a probability of having a TEE of 0 and 17% (95% CI: 10–29), respectively. Patients with GCT are at a higher risk for TEE than patients with non-GCT cancer while on cisplatin-based chemotherapy. This risk can be accurately predicted by serum LDH and body surface area. This predictive index may help to study prospectively the impact of thromboprophylaxis in GCT patients.
doi:10.1038/sj.bjc.6602791
PMCID: PMC2361657  PMID: 16205699
cancer of the testis; chemotherapy; cisplatin; germ-cell tumour; thrombosis
15.  Malignant Germ Cell Tumors Display Common microRNA Profiles Resulting in Global Changes in Expression of mRNA Targets 
Cancer research  2010;70(7):2911-2923.
Despite their extensive clinical and pathological heterogeneity, all malignant germ cell tumors (GCTs) are thought to originate from primordial germ cells. However, no common biological abnormalities have been identified to date. We profiled 615 microRNAs (miRNAs) 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 over-expressed regardless of histological 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 2-7 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 (3′UTR) of mRNAs down-regulated in pediatric malignant GCTs (as a group), YSTs and ECs; and in adult YSTs (all versus non-malignant tissue controls; p<0.05). For the pediatric samples, down-regulated genes containing 3′UTR GCACTT showed significant over-representation of Gene Ontology (GO) terms related to cancer–associated processes, whereas for down-regulated genes lacking GCACTT, GO 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 over-expressed in malignant GCTs and coordinately down-regulate mRNAs involved in biologically significant pathways.
doi:10.1158/0008-5472.CAN-09-3301
PMCID: PMC3000593  PMID: 20332240
AAGUGC; embryonic stem cell; germ cell tumor; miRNA; mRNA
16.  LIN28 expression in malignant germ cell tumors down-regulates let-7 and increases oncogene levels 
Cancer research  2013;73(15):4872-4884.
Despite their clinico-pathologic heterogeneity, malignant germ-cell-tumors (GCTs) share molecular abnormalities that are likely to be functionally important. In this study, we investigated the potential significance of down-regulation of the let-7 family of tumor-suppressor microRNAs in malignant-GCTs. Microarray results from pediatric and adult samples (n=45) showed that LIN28, the negative-regulator of let-7 biogenesis, was abundant in malignant-GCTs, regardless of patient age, tumor site or histologic subtype. Indeed, a strong negative-correlation existed between LIN28 and let-7 levels in specimens with matched datasets. Low let-7 levels were biologically significant, since the sequence complementary to the 2-7nt common let-7 seed ‘GAGGUA’ was enriched in the 3′untranslated regions of mRNAs up-regulated in pediatric and adult malignant-GCTs, compared with normal gonads (a mixture of germ cells and somatic cells). We identified 27 mRNA targets of let-7 that were up-regulated in malignant-GCT cells, confirming significant negative-correlations with let-7 levels. Among 16 mRNAs examined in a largely independent set of specimens by qRT-PCR, we defined negative-associations with let-7e levels for six oncogenes, including MYCN, AURKB, CCNF, RRM2, MKI67 and C12orf5 (when including normal control tissues). Importantly, LIN28 depletion in malignant-GCT cells restored let-7 levels and repressed all of these oncogenic let-7 mRNA targets, with LIN28 levels correlating with cell proliferation and MYCN levels. Conversely, ectopic expression of let-7e was sufficient to reduce proliferation and down-regulate MYCN, AURKB and LIN28, the latter via a double-negative feedback loop. We concluded that the LIN28/let-7 pathway has a critical pathobiological role in malignant-GCTs and therefore offers a promising target for therapeutic intervention.
doi:10.1158/0008-5472.CAN-12-2085
PMCID: PMC3732484  PMID: 23774216
germ cell tumor; let-7; LIN28; microRNA
17.  Incidence patterns and trends of gonadal and extragonadal germ cell tumors in Germany, 1998–2008 
Cancer epidemiology  2013;37(4):370-373.
Background
Gonadal (GGCT) and extragonal germ cell tumors [GCT (EGCT)] are thought to originate from primordial germ cells. In contrast to well reported population-based data of GGCTs in males, analyses of GGCTs in females and EGCTs in both sexes remain limited.
Methods
In a pooling project of nine population-based cancer registries in Germany of the years 1998–2008, 16,883 GCTs and their topographical sites were identified using ICD-O morphology and topography for those aged 15 years and older. We estimated age-specific and age-standardized incidence rates.
Results
Among males, the incidence of testicular GCTs increased over time. In contrast, there was no increase in the incidence of EGCTs. Among females, rates of ovarian GCTs were stable, while rates of EGCTs declined over time. The most frequent extragonadal sites were mediastinum among males and placenta among females.
Conclusions
Our results underline different incidence trends and distinct age-specific incidence patterns of GGCTs and EGCTs, as reported recently by several population-based registries. The differences suggest that GGCTs and EGCTs may have different etiologies.
doi:10.1016/j.canep.2013.04.003
PMCID: PMC4029332  PMID: 23683844
Extragonadal germ cell tumors; germ cell tumors; incidence; cancer registry; testicular neoplasms; ovarian neoplasms
18.  Recent Advances in Granulosa Cell Tumor Ovary: A Review 
Granulosa cell tumors constitute less than 5 % of all ovarian tumors. Unlike epithelial ovarian tumors, they occur in a younger age group, are usually detected in an early stage and often have features of hyperestrogenism. The presenting symptoms are usually nonspecific with abdominal pain or distension. They follow an indolent course and are characterized by a long natural history. Mutation of FOXL2 (402C->G) seen in 97 % of adult GCT may be pathognomonic for adult GCT. Only stage of the disease has been consistently shown in various studies to affect survival of patients with GCT. The initial management of patients, for whom fertility is not an issue, is total abdominal hysterectomy, bilateral salpingo-oophorectomy and removal of all gross disease. Nodal dissection is not a significant factor for survival and is not recommended in surgical staging of GCT. Fertility preserving surgery with unilateral salpingo-oophorectomy is feasible in young patients with stage Ia GCT. Patients with early stage disease (stage I and II) have a very good prognosis with 5 year DFS and OS of 89 % and 99 % respectively and these groups of patients usually don’t require any postoperative treatment. Patients with stage Ic disease associated with poor prognostic factors like large tumor size or high mitotic index and stage II, have a higher chance of relapse, and may benefit with postoperative treatment but role of chemotherapy is still debatable. In advanced stage disease (stage III and IV) the 5 year DFS and OS disease was 72 % and 80 % respectively hence the option of postoperative treatment with 6 cycles of BEP should be considered in this group. Recently paclitaxel is being investigated as an effective tool in GCT. The efficacy of radiation in GCT is not well defined but in optimally debulked cases postoperative radiation is a viable option. Due to high chance of recurrence even years after apparent clinical cure of the primary tumor, lifelong follow up with clinical examination and tumor markers like inhibin B is recommended. About 25 % GCT develop recurrence and the median time to recur is usually 4–5 years. Most recurrences are intraperitoneal and usually a complete debulking of the disease is feasible even in the recurrent setting. Postoperative chemotherapy (platinum based) is usually given after surgery more so in cases with widespread disease or after suboptimal cytoreduction. Recurrent chemoresistant, progressive non-responding GCT or patients with high surgical risk are ideal candidates for targeted therapy.
doi:10.1007/s13193-012-0201-z
PMCID: PMC3578540  PMID: 24426698
Granulosa cell tumor; Inhibin B
19.  Resistance to Platinum-Containing Chemotherapy in Testicular Germ Cell Tumors Is Associated with Downregulation of the Protein Kinase SRPK11 
Neoplasia (New York, N.Y.)  2004;6(4):297-301.
Abstract
Male germ cell tumors (GCTs) are extremely sensitive to platinum-containing chemotherapy, with only 10% of patients showing therapy resistance. However, the biological basis of the high curability of disseminated GCTs by chemotherapy is still unknown. Recently, we demonstrated that the mammalian serine/arginine-rich protein-specific kinase 1 (SRPK1) is a cisplatin-sensitive gene, inactivation of which leads to cisplatin resistance. Because, in mammalians, the expression of SRPK1 is preferentially high in testicular tissues, cisplatin responsiveness of male GCTs might be associated with SRPK1 levels. In the present study, we monitored SRPK1 protein expression in a unique series of nonseminomatous GCTs by immunohistochemistry. Randomly selected GCTs (n = 70) and tumors from patients responding to standard chemotherapy (n = 20) generally showed strong SRPK1 staining. In contrast, expression in refractory GCTs (n = 20) as well as in GCTs from poor-prognosis patients responding to high-dose chemotherapy only (n = 11) was significantly lower (two-sided Wilcoxon rank sum test: P < .001). In conclusion, our data suggest that SRPK1 expression might be an important prognostic indicator for the chemoresponsiveness of nonseminomatous GCTs.
PMCID: PMC1502111  PMID: 15256051
Chemotherapy resistance; germ cell tumors; chemotherapy sensitivity; protein kinase SRPK1; immunohistochemistry
20.  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.
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/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.
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.
doi:10.1186/1471-2164-11-132
PMCID: PMC2837036  PMID: 20178649
21.  Primary CNS germ cell tumors in Japan and the United States: an analysis of 4 tumor registries 
Neuro-Oncology  2012;14(9):1194-1200.
Intracranial germ cell tumors (GCTs) are relatively rare. Their incidence has been considered to be higher in East Asia than in the United States. This study estimates the incidence of CNS GCTs in Japan and the United States, investigates gender discrepancies in each country, and describes treatment outcomes. Data on primary CNS GCTs from 4 databases were utilized: population-based malignant incidence data from (1) the Japan Cancer Surveillance Research Group (2004–2006; 14 registries), malignant and nonmalignant incidence data from (2) the Surveillance, Epidemiology, and End Results Program (2004–2008; 17 registries), and hospital-based observed survival data from (3) the Brain Tumor Registry of Japan (1984–2000) and (4) the US National Cancer Data Base (1990–2003). Incidence rates per 100 000 for malignant GCTs were not statistically significantly different between Japan (males = 0.143, females = 0.046) and the United States (males = 0.118, females = 0.030). The malignant incidence-rate ratio was higher for pineal GCTs versus nonpineal (ie, the rest of the brain) GCTs in Japan (11.5:1 vs 1.9:1, respectively) and the United States (16.0:1 vs 1.7:1, respectively). In general, 5-year survival estimates were high: over 75% for all GCTs, and over 81% for germinomas, regardless of the type of treatment in either Japan or the United States. The incidence of primary GCTs is similar between Japan and the United States and has the same gender-based patterns by location. High rates of survival were observed in both countries.
doi:10.1093/neuonc/nos155
PMCID: PMC3424216  PMID: 22869621
brain tumor; epidemiology; germ cell tumors; germinoma; mixed germ cell tumors; pineal gland; teratoma; tumor registry
22.  Mediastinal Germ Cell Tumors with an Angiosarcomatous Component: A Report of 12 Cases 
Human pathology  2010;41(6):832-837.
The development of an angiosarcomatous component in germ cell tumors (GCTs) is rare. Here we studied 12 cases of mediastinal GCTs with an angiosarcomatous component. All patients were men with a mean age of 34 years (range, 24 to 49 years). No patient had a documented testicular GCT. The mean size of mediastinal tumors was 12.9 cm (range, 5.5 to 16.0 cm). Grossly, the tumors were cystic with variegated hemorrhagic, mucinous and fleshy solid areas. Microscopically, all tumors were composed of GCT. The most common GCT component was teratoma (n=10), and other GCT components included seminoma (n=3), yolk sac tumor (n=3), embryonal carcinoma (n=2) and choriocarcinoma (n=1). The angiosarcomatous component was present in primary mediastinal tumors (n=6), metastasis (n=3), or both primary mediastinal tumor and metastasis (n=3). The angiosarcomatous component accounted for an average of 30% (range, 5% to 95%) of the primary mediastinal tumor. In addition, other non–germ cell components, including rhabdomyosarcoma (n = 3), leiomyosarcoma (n = 1), and poorly differentiated carcinoma (n = 1), were also present in the tumors. Of the 10 patients with follow-up available, all patients developed metastasis (n=8) or local recurrence (n=2); seven died of disease at a mean of 33 months (range, 21 to 75 months), and three patients were alive at a mean of 75 months (range, 5 to 120 months). Our findings suggest that the presence of an angiosarcomatous component in mediastinal GCT, even in a small amount, is associated with a poor clinical outcome.
doi:10.1016/j.humpath.2009.11.008
PMCID: PMC4163004  PMID: 20153508
germ cell tumor; mediastinum; sarcomatoid transformation; angiosarcoma
23.  Identification of a Heritable Model of Testicular Germ Cell Tumor in the Zebrafish 
Zebrafish  2009;6(4):319-327.
Abstract
Germ cell tumors (GCTs) affect infants, children, and adults and are the most common cancer type in young men. Progress in understanding the molecular basis of GCTs has been hampered by a lack of suitable animal models. Here we report the identification of a zebrafish model of highly penetrant, heritable testicular GCT isolated as part of a forward genetic screen for cancer susceptibility genes. The mutant line develops spontaneous testicular tumors at a median age of 7 months, and pedigree analysis indicates dominant inheritance of the GCT susceptibility trait. The zebrafish model exhibits disruption of testicular tissue architecture and the accumulation of primitive, spermatogonial-like cells with loss of spermatocytic differentiation. Radiation treatment leads to apoptosis of the tumor cells and tumor regression. The GCT-susceptible line can serve as a model for understanding the mechanisms regulating germ cells in normal development and disease and as a platform investigating new therapeutic approaches for GCTs.
doi:10.1089/zeb.2009.0613
PMCID: PMC2811880  PMID: 20047465
24.  The epidemiology of malignant giant cell tumors of bone: an analysis of data from the Surveillance, Epidemiology and End Results Program (1975–2004) 
Rare Tumors  2009;1(2):e52.
Malignant giant cell tumor (GCT) of bone is a rare tumor with debilitating consequences. Patients with GCT of bone typically present with mechanical difficulty and pain as a result of bone destruction and are at an increased risk for fracture. Because of its unusual occurrence, little is known about the epidemiology of malignant GCT of bone. This report offers the first reliable population-based estimates of incidence, patient demographics, treatment course and survival for malignancy in GCT of bone in the United States. Using data from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) program, we estimated the overall incidence and determinants of survival among patients diagnosed with malignant GCT of bone from 1975–2004. Cox proportional hazards regression was used to evaluate demographic and clinical determinants of survival among malignant GCT cases. Based on analyses of 117 malignant GCT cases, the estimated annual incidence in the United States was 1.6 per 10,000,000 persons per year. Incidence was highest among adults aged 20 to 44 years (2.4 per 10,000,000 per year) and most patients were diagnosed with localized (31.6%) or regional (29.9%) disease compared to distant disease (16.2%). Approximately 85% of patients survived at least 5 years, with survival poorest among older patients and those with evidence of distant metastases at time of diagnosis. The current study represents the largest systematic investigation examining the occurrence and distribution of malignancy in GCT of bone in the general U.S. population. We confirm its rare occurrence and suggest that age and stage at diagnosis are strongly associated with long-term survival.
doi:10.4081/rt.2009.e52
PMCID: PMC2994468  PMID: 21139931
giant cell tumor of bone; surveillance; epidemiology and end results; descriptive epidemiology; incidence; survival; osteosarcoma.
25.  Factors Associated with Delayed Cancer Diagnosis in Egyptian Children 
BACKGROUND
Despite tremendous importance of early cancer diagnosis in children, few studies on this topic have been conducted in Egypt. Early stage diagnosis can have a positive effect on prognoses and the quality of life of children with cancer. We investigated delays in the diagnosis of childhood cancers in Egypt and determined the factors associated with these delays.
METHODS
This retrospective study included 172 children with cancer from two pediatric oncology units. The interval between symptoms onset and final diagnosis for each child was estimated and examined by univariate and multivariate analyses to determine correlations with the child’s sex, age at diagnosis, type and site of malignancy, family residence, socioeconomic status, and parental educational level.
FINDINGS
The median total diagnosis delay period was 47 days caused by patients and/or parents (8 days) and diagnosis (28 days). Statistically significant patient factors associated with delayed diagnosis were age (<5 years), lower parental education, and socioeconomic status. Sex residence and family size were not significant. Malignancy type and tumor site significantly affected the time for diagnosis. The lowest median value was associated with germ cell tumors (GCTs) and leukemia, and the highest value was in children with brain tumor. Missed diagnoses were initially recorded in 39.5% of the patients and were associated with patient and tumor factors.
INTERPRETATION
Delayed diagnosis of childhood cancer is related to age, family, socioeconomic status and parental education, and cancer type and site. Efforts should be made to promote awareness, develop effective steps to eliminate possible contributing factors, and determine the best intervention method.
doi:10.4137/CMPed.S16413
PMCID: PMC4159362  PMID: 25232287
delayed diagnosis; cancer; children; Egypt

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