Germ Cell Tumors Of Adolescents Research Articles

Primary intracranial germ cell tumors in adolescents and adults: Results of an international, multicenter, retrospective cohort study.

2061 Background: Primary Intracranial Germ Cell Tumors (iGCT) are rare. Previous prospective and retrospective studies mainly included pediatric patients (pts) with a median age of 10-14 years. The aim of this retrospective analysis was to evaluate characteristics, treatment and outcome of adolescents and adults with iGCT. Methods: Data were collected from 10 institutions in Germany and Switzerland. Pts aged >/= 16 years at first diagnosis or at relapse with a primary iGCT were included. Objective responses were evaluated by local investigators. Statistics (Cox proportional hazard model, progression-free survival (PFS) and overall survival (OS) analyzed by Kaplan-Meier method) were performed with SPSS v29. Results: We identified 75 pts (92.0% male) with a median age of 23 years (range 16-60, 94.7% >/= 18 years). At first diagnosis, histology was pure germinoma in 70.7%, pure teratoma in 10.7%, other non-germinomatous GCT (NGGCT) in 13.3%, unknown in 5.3% of pts. Localized, bifocal, and metastatic disease was found in 72.0, 6.7, and 21.3% of pts. As part of their first line (1L) treatment, 69.3%, 80.0%, and 62.7% received surgery, radiotherapy, and chemotherapy, respectively. High dose chemotherapy/ autologous stem cell transplantation (HDCT/ASCT) was part of 1L treatment in n=3 pts with NGGCT. Trimodal and bimodal treatment was performed in 48.0% and 32.0% of pts. Response to 1L therapy was complete remission (CR) in 61.3%, partial remission tumor marker negative (PRm-) in 16.0%, PRm+ in 4.0%, PR with tumor marker status unknown in 4.0%, progressive disease (PD) in 2.7%, and unknown in 12.0%. Relapse occurred in 13/75 pts (17.3%) with unknown histology (n=4), teratoma (n=2), other NGGCT (n=4), and germinoma (n=3). In 2 pts. in whom germinoma was diagnosed at time of first diagnosis, at time of recurrence PNET and Yolk sac tumor were histologically proven. Median time to relapse was 19.0 months (mo.; range 3-223). HDCT/ASCT as salvage treatment was performed in 5 pts with NGGCT and in one pt with germinoma as 2L (n=5) or 3L (n=1). NGGCT histology was associated with increased risk for recurrence or death (p=0.012 and 0.039).3-year PFS was 90.7% (germinoma: 98.1%, NGGCT: 73.9%) and 5-year OS was 92.0% (germinoma: 98.1%; NGGCT: 78.3%). Median follow-up time was 60 mo (range 0-339). Conclusions: Disease characteristics, treatment and outcomes of adolescent/ adult iGCT pts are comparable to those reported in pediatric pts. High cure rates are achieved in pts with pure germinoma and current treatment concepts. In pts with NGGCT further investigation is needed to improve survival outcomes.

Clinical characteristics of malignant germ cell tumors in adolescents: A multicenter 10-year retrospective study in Beijing.

The aim of this study was to review clinical features of adolescent malignant germ cell tumors (MGCTs) in Beijing and analyze the peculiar characteristics of this age group. Clinical characteristics, pathological presentations, and survival outcomes of 34 patients were analyzed retrospectively. Of 34 patients, 12 girls and 22 boys, 18 (52.9%) had an extra-cranial tumor, including one testicular tumor, five ovarian tumors, one sacrococcygeal tumor, and 11 mediastinal tumors. Histologically, we found immature teratomas (n = 6), yolk sac tumors (n = 5), mixed malignant tumors (n = 5), an embryonic carcinoma (n = 1), and seminoma (n = 1). Three-year event-free survival (EFS) and overall survival (OS) were 48.8% and 62.9%, respectively. Another 16 (47.1%) patients had an intracranial tumor, including nine in the pineal region, five in the suprasellar region, one in basal ganglia, and one in cerebellopontine. All patients had localized disease and an excellent outcome with 3-year EFS and OS of 93.7% and 100%, respectively. Adolescent MGCTs are rare with a strong dependence on gender, and the mediastina and pineal region are the most common tumor locations. The prognosis is promising compared with that of other adolescent tumors and MGCTs in other age groups. MGCTs in mediastina have a tendency to companion with other hematological malignancies, and the prognosis is extremely poor in these patients.

Resection of Residual Masses After Chemotherapy for Metastatic Nonseminomatous Germ Cell Tumors in Adolescents and Adults.

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in the Journal of Clinical Oncology, to patients seen in their own clinical practice.Optimal treatment of patients with testicular germ cell tumors requires a coordinated multidisciplinary approach, so that surgery, chemotherapy, and, when appropriate, radiation therapy can be integrated into a coherent and comprehensive treatment plan. Nonseminomatous germ cell tumors (NSGCT) are often a mixture of teratoma and cancer (choriocarcinoma, embryonal carcinoma, seminoma, and/or yolk sac tumor). While the cancers are highly sensitive to and often cured by chemotherapy, teratoma is resistant to chemotherapy and radiation therapy and generally must be resected surgically to be successfully treated. Therefore, the standard of care for metastatic NSGCT is to resect all resectable residual masses after chemotherapy. If such resection reveals only teratoma and/or necrosis/fibrosis, then patients are put on a surveillance schedule to monitor for relapse. If viable cancer is found and there are positive margins or 10% or more of any of the residual masses consists of viable cancer, then two cycles of adjuvant chemotherapy should be considered.

Associations between birth defects and childhood and adolescent germ cell tumors according to sex, histologic subtype, and site.

Studies have reported increased rates of birth defects among children with germ cell tumors (GCTs). However, few studies have evaluated associations by sex, type of defect, or tumor characteristics. Birth defect-GCT associations were evaluated among pediatric patients (N = 552) with GCTs enrolled in the Germ Cell Tumor Epidemiology Study and population-based controls (N = 6380) without cancer from the Genetic Overlap Between Anomalies and Cancer in Kids Study. The odds ratio (OR) and 95% confidence interval (CI) of GCTs according to birth defects status were estimated by using unconditional logistic regression. All defects were considered collectively and by genetic and chromosomal syndromes and nonsyndromic defects. Stratification was by sex, tumor histology (yolk sac tumor, teratoma, germinoma, and mixed/other), and location (gonadal, extragonadal, and intracranial). Birth defects and syndromic defects were more common among GCT cases than controls (6.9% vs. 4.0% and 2.7% vs. 0.2%, respectively; both p < .001). In multivariable models, GCT risk was increased among children with birth defects (OR, 1.7; 95% CI, 1.3-2.4) and syndromic defects (OR, 10.4; 95% CI, 4.9-22.1). When stratified by tumor characteristics, birth defects were associated with yolk sac tumors (OR, 2.7; 95% CI, 1.3-5.0) and mixed/other histologies (OR, 2.1; 95% CI, 1.2-3.5) and both gonadal tumors (OR, 1.7; 95% CI, 1.0-2.7) and extragonadal tumors (OR, 3.8; 95% CI, 2.1-6.5). Nonsyndromic defects specifically were not associated with GCTs. In sex-stratified analyses, associations were observed among males but not females. These data suggest that males with syndromic birth defects are at an increased risk of pediatric GCTs, whereasmales with nonsyndromic defects and females are not at an increased risk. We investigated whether birth defects (such as congenital heart disease or Down syndrome) are linked to childhood germ cell tumors (GCTs), cancers that mainly develop in the ovaries or testes. We studied different types of birth defects (defects that were caused by chromosome changes such as Down syndrome or Klinefelter syndrome and defects that were not) and different types of GCTs. Only chromosome changes such as Down syndrome or Klinefelter syndrome were linked to GCTs. Our study suggests that most children with birth defects are not at an increased risk of GCTs because most birth defects are not caused by chromosome changes.

EANO, SNO and Euracan consensus review on the current management and future development of intracranial germ cell tumors in adolescents and young adults.

The incidence of intracranial germ cell tumors (iGCT) is much lower in European and North American (E&NA) than in Asian population. However, E&NA cooperative groups have simultaneously developed with success treatment strategies with specific attention paid to long-term sequelae. Neurological sequelae may be reduced by establishing a diagnosis with an endoscopic biopsy and/or cerebrospinal fluid (CSF) and/or serum analysis, deferring the need to perform a radical surgery. Depending on markers and/or histological characteristics, patients are treated as either germinoma or non-germinomatous germ cell tumors (NGGCT). Metastatic disease is defined by a positive CSF cytology and/or distant drops in craniospinal MRI. The combination of surgery and/or chemotherapy and radiation therapy is tailored according to grouping and staging. With more than 90% 5-year event-free survival (EFS), localized germinomas can be managed without aggressive surgery, and benefit from chemotherapy followed by whole ventricular irradiation with local boost. Bifocal germinomas are treated as non-metastatic entities. Metastatic germinomas may be cured with craniospinal irradiation. With a 5-year EFS over 70%, NGGCT benefit from chemotherapy followed by delayed surgery in case of residual disease, and some form of radiotherapy. Future strategies will aim at decreasing long-term side effects while preserving high cure rates.

Primary Mediastinal and Testicular Germ Cell Tumors in Adolescents and Adults: A Comparison of Genomic Alterations and Clinical Implications.

Simple SummaryThe germ cell tumors (GCTs) family is a heterogeneous group of neoplasms that includes tumors affecting testis (TGCTs) and rarer cases occurring in extragonadal sites. Mediastinal germ cell tumors (MGCTs) are more aggressive and have poorer prognosis. Due to their rarity of MGCTs, few molecular and clinical studies are reported. MGCTs share biological similarities with TGCT, and international guidelines recommend use of the same therapies validated for TGCT. However, while high response rate is achieved in TGCT, MGCT tend to be resistant to therapy. This review resumes all molecular findings reported in MGCTs, summarizing molecular characteristics common with TGCT and highlighting the different molecular alterations that characterize mediastinal tumors. A deeper understanding of the MGCT biology will help in clinical management of these patients.Mediastinal germ cell tumors (MGCTs) share histologic, molecular and biomarkers features with testicular GCTs; however, nonseminomatous MGCTs are usually more aggressive and have poorer prognosis than nonseminomatous TGCTs. Most nonseminomatous MGCT cases show early resistance to platinum-based therapies and seldom have been associated with the onset of one or more concomitant somatic malignancies, in particular myeloid neoplasms with recent findings supporting a common, shared genetic precursor with the primary MGCT. Genomic, transcriptomic and epigenetic features of testicular GCTs have been extensively studied, allowing for the understanding of GCT development and transformation of seminomatous and nonseminomatous histologies. However, MGCTs are still lacking proper multi-omics analysis and only few data are reported in the literature. Understanding of the mechanism involved in the development, in the progression and in their higher resistance to common therapies is still poorly understood. With this review, we aim to collect all molecular findings reported in this rare disease, resuming the similarities and disparities with the gonadal counterparts.

Intracranial Germ Cell Tumors in Adolescents and Young Adults: A 40-Year Multi-Institutional Review of Outcomes

The aim of this study was to determine the practice patterns and outcomes of intracranial germ cell tumors (IGCT) in adolescents and young adults according to different therapeutic approaches. One-hundred twelve patients with IGCT aged 15 to 39 years were managed at either XX or the XY center from 1975 to 2015. The charts were retrospectively reviewed and data collected. Median duration of follow-up was 8.3 years. Ninety-four patients had germinomas, and 18 had nongerminomatous germ cell tumors (NGGCT). The primary disease sites were pineal gland (37 of 94 germinoma, 14 of 18 NGGCT) and suprasellar region (23 of 94 germinoma, 2 of 18 NGGCT). Eleven patients with germinoma (12%) and 2 patients with NGGCT (11%) had radiographic spinal metastases or positive lumbar cerebrospinal fluid cytology. Event-free survival (EFS) was 84% and overall survival (OS) was 90% at 10 years for germinoma; EFS was 71% and OS was 86% at 10 years for NGGCT. For patients with germinoma, 10-year EFS was 100% after craniospinal radiation therapy (CSRT) with chemotherapy (N = 10); 100% after whole-ventricular radiation therapy (WVRT), whole-brain radiation therapy (WBRT), or focal radiation therapy (FRT) with chemotherapy (N = 22); 90% after CSRT alone (N = 46); and 41% after WVRT, WBRT, or FRT alone (N = 16) (P < .0005). Ten-year OS was 100%, 100%, 90%, and 72%, respectively (P = .032). For patients with NGGCT, 10-year EFS was 80% after CSRT, WBRT, or WVRT plus chemotherapy (N = 10) versus 58% after FRT plus chemotherapy (N = 8) (P = .31); 10-year OS was 90% versus 58%, respectively (P = .16). We report excellent overall outcomes according to treatment approach in the largest study of IGCT in adolescents and young adults to our knowledge. EFS and OS were inferior after non-CSRT without chemotherapy in germinoma.

Germ Cell Tumors in Adolescents and Young Adults

Germ cell tumors (GCTs) are rare in childhood, representing only 3.5% of childhood cancers, but a common malignancy in adolescents and young adults (AYAs), accounting for 13.9% of neoplasms in adolescents between age 15 and 19 years. The overall outcomes of patients treated for GCTs are excellent. However, as seen in other cancers, outcomes for AYA patients are significantly worse. Understanding the reasons for this observation has led to different approaches to diagnosis, staging, and treatment. The Malignant Germ Cell International Consortium was created to bring together pediatric, gynecologic, and testicular cancer specialists to promote research initiatives and provide evidence-based approaches in the management of GCTs across different age groups. Collaboration between multiple subspecialties is essential to further understand the disease continuum, the underlying biologic characteristics, and the development of appropriate therapeutic approaches. This review focuses on the unique characteristics of patients with extracranial GCTs in the AYA group.

Chromosomal gains of 12p and 1q are not associated with inferior outcome of pediatric and adolescent germ cell tumors.

Pediatric germ cell tumors (GCT) are rare and very heterogeneous neoplasms that show a high diversity in tumor biology and histology. The clinical behavior cannot be predicted based on morphology or immunohistochemistry. The aim of this study was to investigate a large number of pediatric GCT regarding chromosomal gains of 12p and 1q. One hundred and eighty pediatric nonseminomatous GCT, that is, mature teratomas, immature teratomas, yolk sac tumors, and mixed germ cell tumors, from three age groups were evaluated for 1q and 12p gains by fluorescence in situ hybridization in tissue micro arrays. The results were correlated with tumor biology and clinical data. Eleven out of 143 GCT showed gains of 1q. In 29/157 GCT a gain of 12p was found. Prepubertal patients (≤6 years of age) more often displayed gains of 1q compared to pubertal/adolescent patients (11-17 years of age), whereas pubertal/adolescent patients showed gains of 12p most frequently. Twenty-one out of 155 patients suffered from relapse or metachronous disease. Patients with and without gains of 1q or 12p did not differ in frequency of these events. However, the likelihood of occurrence of these clinical events varied depending on the histological type of the tumor. The biological behavior of pediatric GCT depends more on the histological type of the tumor than on the genetic aberrations examined in this study. Gains of 1q and 12p are not suitable to predict the clinical outcome of GCT in childhood. Nevertheless, both genetic alterations might be used as biomarkers to distinguish different histological types of GCT and therefore could be of diagnostic value, especially in borderline cases.

Canadian patterns of practice for intracranial germ cell tumors in adolescents and young adults

The study objectives were to describe patterns of practice for intracranial germ cell tumors (IGCT) in adolescents and young adults (AYA) and to determine factors associated with practice patterns. A survey was written containing questions on the management of two 17-year old males, one with localized pineal germinoma and the other with localized pineal non-germinomatous germ cell tumor (NGGCT). An invitation to participate anonymously in the survey was e-mailed to 119 oncologists who treat brain tumors across Canada. Seventy-two (61%) of the 119 oncologists participated in the study. For the germinoma case, the most common treatment approaches were whole ventricular radiotherapy (WVRT) and chemotherapy (CH) (56%), WVRT alone (15%), and craniospinal radiotherapy (CSRT) alone (10%); for physicians recommending WVRT + CH, most frequently selected whole ventricular doses were 24Gy (57%) and 18Gy (20%). Chemotherapy was included in the treatment of germinoma by 96% of pediatric physicians vs. 54% of adult physicians (P = 0.001). The most common treatment approaches for NGGCT were CSRT + CH (44%), WVRT + CH (21%), and pineal gland RT + CH (15%). The selection of craniospinal vs. smaller-volume RT was not associated with the physicians' specialty, percentage of practice treating brain tumors, number of IGCTs seen, or size of institution. There is wide variation in the management of IGCT in AYA across Canada. A 17-year old male with a localized pineal germinoma is highly likely to receive chemotherapy if managed by a pediatric oncologist, while the same patient is much less likely to receive chemotherapy if managed by an adult oncologist.

Canadian Patterns of Practice for Intracranial Germ Cell Tumors in Adolescents and Young Adults

To describe Canadian patterns of practice for intracranial germ cell tumors (IGCT) in adolescents and young adults (AYA), and to determine factors associated with treatment approaches in this disease.

Germ Cell Tumors in Adolescents and Young Adults.

Germ cell tumors (GCTs) represent a group of biologically complex malignancies that affect patients at different sites within the body and at different ages. The varying nature of these tumors reflects their cell of origin which is the primordial germ cell, which normally gives rise to ovarian and testicular egg and sperm producing cells. These cells retain an ability to give rise to all types of human tissues, and this is illustrated by the different kinds of GCTs that occur. In adolescent and young adult (AYA) patients, GCTs predominantly present as testicular, ovarian or mediastinal primary GCTs, and represent some of the most complex therapeutic challenges within any AYA practice. The varying types of GCTs, defined by primary site and/or age at presentation, can look very similar microscopically. However, there is growing evidence that they may have different molecular characteristics, different biology and different requirements for curative treatments. Whilst in adult testicular GCTs there is evidence for an environmental cause during fetal development and a genetic component, these causative factors are much less well understood in other GCTs. GCTs are some of the most curable cancers in adults, but some patients exhibit resistance to standard treatments. Because of this, today's clinical research is directed at understanding how to best utilize toxic therapies and promote healthy survivorship. This chapter explores the biology, behavior and treatment of GCTs and discusses how the AYA group of GCTs may hold some of the keys to understanding fundamental unanswered questions of biological variance and curability in GCTs.

Testicular germ cell tumors in adolescents - results of the protocol MAHO 98 and the identification of good risk patients.

In adolescents aged 10-15 years germ cell tumors of the testis (TGCT) are rare and information for a risk adapted therapy limited. The protocol MAHO 98 for patients (pts) with TGCTs is stratified according to age, stage and histology. Pts ≥ 10 years received after tumororchiectomy 2 courses (crs) PVB and restaging. Residual tumor was resected and therapy continued in regard to inital stage and response. Chemotherapy: PVB: cisplatin (20 mg/m²/day 1-5), vinblastine (3 mg/m²/day 1+2), and bleomycin (15 U/m²/day 1-3). For consolidation 1 crs PVB has been given to stage II patients with CR. In case of PR, 2 crs PEB (vinblastine substituted by etoposide 100 mg/m²/day 1-3) or relapse 3 crs PEI (bleomycin substituted by ifosfamide 1 500 mg/m²/day 1-5) were given. Between Jan 1998 and Dec 2005, 34 pts (≥ 10 year) were registered, 31 fulfilled the inclusion criteria. Median age: 15;6 years; months (range 13;5-20;2 ). Lugano staging: IA n=14, IB n=2, IC n=3, IIA n=4, IIB n=6, IIC n=1, IIIC n=1. The stage IIIC pt received preoperative chemotherapy, all other pts had tumororchiectomy first. Residual tumor after 2 crs PVB was detected in 4 pts and was resected. Late relapses occurred in 2 pts and were cured by additional therapy. All patients are surviving. Young patients with TGCT stage I and II have an excellent prognosis and further reduction of therapy has to be considered.

Absence of BRAF mutation in pediatric and adolescent germ cell tumors indicate biological differences to adult tumors

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.

Analysis of the adenomatous polyposis coli (APC) gene in childhood and adolescent germ cell tumors

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). 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. 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. 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.

Seladin‐1 and testicular germ cell tumours: new insights into cisplatin responsiveness

The molecular basis for the exquisite sensitivity of testicular germ cell tumours of adolescents and adults (TGCTs), ie seminomas and non-seminomatous germ cell tumours, to chemo/radiotherapy has not been fully clarified so far. It has been suggested that it may be dependent on factors involved in the regulation of apoptosis. Seladin-1 is a multi-functional protein involved in various biological processes, including apoptosis. The aim of our study was to assess the expression of seladin-1 in different histological types of TGCTs, known to have varying treatment sensitivity, in order to establish whether this protein may influence cisplatin responsiveness in vitro. Seladin-1 expression levels, both at the mRNA and at the protein level, were higher in the adjacent normal parenchyma than in the pathological counterparts. In tumoural tissues, the level of expression differed among TGCT histological types. The highest tumour-expression level was found in teratoma, whereas the lowest was detected in seminoma, corresponding to the different chemo/and radiosensitivities of these tumour types. In common with other cancers, in TGCT-derived cell lines seladin-1 showed anti-apoptotic properties through inhibition of caspase-3 activation. We confirmed our results using a non-seminomatous cell line model (NT2) before and after differentiation with retinoic acid. Significantly higher seladin-1 expression was observed in the differentiated derivatives (teratoma) and an inverse relationship was found between seladin-1 expression and the amount of cleaved caspase-3. Seladin-1 silencing or overexpression in this cell line supports involvement of seladin-1 in cisplatin responsiveness. Seladin-1 silencing was associated with greater cisplatin responsiveness demonstrated by decreased cell viability and increased expression of apoptotic markers. In contrast, overexpression of seladin-1 was associated with a higher survival rate and a clear anti-apoptotic effect. In conclusion, we have demonstrated for the first time an important role for seladin-1 in the biology of TGCTs and provided new insights into cisplatin responsiveness of these tumours.

Embryogenesis and Metastatic Testicular Germ Cell Tumors of Adolescents

This issue of Klinische Padiatrie contains two highly interesting contributions to the field of clinical management of human germ cell tumors of adolescents and young adults [1] [4]. Although both cases in fact relate to metastatic disease, they also show the benefit and relevance of early diagnosis of this particular type of cancer. Testicular germ cell tumors of adolescents and young adults are the seminomas and nonseminomas, also referred to type II TGCTs [17] [20]. Histologically, the nonseminomas are divided into the stem cell component, known as embryonal carcinoma, the yolk sac tumor and choriocarcinoma [extra-embryonal elements], and teratoma [somatic differentiation]. In other words, these tumors show similarities to early embryogenesis, and are in fact really totipotent. They have unique epidemiological characteristics [11] [13]. In fact, they are one of the few solid cancers in adolescents and young adults [2], and represent the most frequent solid tumor in the age group of 15–45 years in the Caucasian population. The cells of origin is the malignant counterpart of an embryonic germ cell, either a primordial germ cell or gonocyte, known as carcinoma in situ(CIS) [18], intratubular germ cell neoplasia unclassified [20], or testicular intratubular neoplasia (TIN) [7]. Specific risk factors for this type of cancer are identified, amongst others cryptorchidism, sub- and infertility, familial predisposition and certain variants of disorders of sex development [6], all related to a delayed maturation of primordial germ cells/gonocytes into pre-spermatogonia. This has been suggested to be part of the so-called testicular dysgenesis syndrome [19]. Invasive TGCTs are characterized on the chromosomal level by gain of the short arm of chromosome 12, mainly due to isochromosome 12p formation [17], which interestingly can also be identified in human embryonic stem cells, grown in vitro [8]. TGCTs are exceptional because of the fact that they can be effectively treated, using a combinatory strategy of surgery, irradiation and/or chemotherapy in most cases [12]. In fact, overall, they are highly sensitive to DNA damaging agents, which can be related to their embryonic origin. However, this specific sensitivity is lost in the mature teratomas, which indeed have no embryonic characteristics anymore, and are in that context similar to normal adult tissue [14] [15], and therefore need surgical intervention for sure. In spite of this sensitivity, it has become obvious that late effects of chemotherapy exposure at young age occur [10]. This has initiated further studies on limiting exposure thereby reducing these side effects. Another clinical obstacle is development of refractory disease, which is often the cause of death of patients with this disease, because of highly limited treatment options [3] [9] [16].

Recent developments in testicular germ cell tumor research

Testicular germ cell tumors of adolescents and adults (TGCTs; the so-called type II variant) are the most frequent malignancies found in Caucasian males between 20 and 40 years of age. The incidence has increased over the last decades. TGCTs are divided into seminomas and nonseminomas, the latter consisting of the subgroups embryonal carcinoma, yolk-sac tumor, teratoma, and choriocarcinoma. The pathogenesis starts in utero, involving primordial germ cells/gonocytes that are blocked in their differentiation, and develops via the precursor lesion carcinoma in situ toward invasiveness. TGCTs are totipotent and can be considered as stem cell tumors. The developmental capacity of their cell of origin, the primordial germ cells/gonocyte, is demonstrated by the different tumor histologies of the invasive TGCTs. Seminoma represents the germ cell lineage, and embryonal carcinoma is the undifferentiated component, being the stem cell population of the nonseminomas. Somatic differentiation is seen in the teratomas (all lineages), whereas yolk-sac tumors and choriocarcinoma represent extra-embryonal differentiation. Seminomas are highly sensitive to irradiation and (DNA damaging) chemotherapy, whereas most nonseminomatous elements are less susceptible to radiation, although still sensitive to chemotherapy, with the exception of teratoma. To allow early diagnosis and follow up, appropriate markers are mandatory to discriminate between the different subgroups. In this review, a summary will be given related to several recent developments in TGCT research, especially selected because of their putative clinical impact.

Genes, chromosomes and the development of testicular germ cell tumors of adolescents and adults

Testicular germ cell tumors (TGCTs) of adults and adolescents are thought to be derived from primordial germ cells or gonocytes. TGCTs develop postpuberty from precursor lesions known as intratubular germ cell neoplasia undifferentiated. The tumors can be divided into two groups based on their histology and clinical behavior; seminomas resemble primordial germ cells or gonocytes and nonseminomas resemble embryonic or extraembryonic tissues at various stages of differentiation. The most undifferentiated form of nonseminoma, embryonal carcinoma, resembles embryonic stem cells in terms of morphology and expression profiling, both mRNAs and microRNAs. Evidence supports both environmental factors and genetic predisposition underlying the development of TGCTs. Various models of development have been proposed and are discussed. In TGCTs, gain of material from the short arm of chromosome 12 is invariable: genes from this region include the proto-oncogene KRAS, which has activating mutations in approximately 10% of tumors or is frequently overexpressed. A number of different approaches to increase the understanding of the development and progression of TGCTs have highlighted the involvement of KIT, RAS/RAF/MAPK, STAT, and PI3K/AKT signaling. We review the role of these signaling pathways in this process and the potential influence of environmental factors in the development of TGCTs.

Differential expression of SOX17 and SOX2 in germ cells and stem cells has biological and clinical implications

Combined action of SOX and POU families of transcription factors plays major roles in embryonic development. In embryonic stem cells, the combination of SOX2 and POU5F1 (OCT3/4) is essential for maintaining the undifferentiated state by activating pluripotency-linked genes, and inhibition of genes involved in differentiation. Besides embryonic stem cells, POU5F1 is also present in early germ cells, primordial germ cells, and gonocytes, where it has a role in suppression of apoptosis. Here we demonstrate that SOX2 is absent in germ cells of human fetal gonads, and as expected carcinoma in situ (CIS), ie the precursor lesion of testicular germ cell tumours of adolescents and adults (TGCTs), and seminoma. Based on genome-wide expression profiling, SOX17 was found to be present, instead of SOX2, in early germ cells and their malignant counterparts, CIS and seminoma. Immunohistochemistry, western blot analysis, and quantitative RT-PCR showed that SOX17 is a suitable marker to distinguish seminoma from embryonal carcinoma, confirmed in representative cell lines. Aberrant SOX2 expression can be present in Sertoli cells when associated with CIS, which can be misdiagnosed as embryonal carcinoma. In conclusion, this study demonstrates the absence of SOX2 in human embryonic and malignant germ cells, which express SOX17 in conjunction with POU5F1. This finding has both diagnostic and developmental biological implications. It allows the identification of seminoma-like cells from embryonal carcinoma based on a positive marker and might be the explanation for the different function of POU5F1 in normal and malignant germ cells versus embryonic stem cells.