Germ Cell Tumors: Looking to the Future

2015 ◽  
pp. e253-e258
Author(s):  
George J. Bosl
Keyword(s):  
Germ Cell ◽  
Primordial Germ Cells ◽  
Tumor Biology ◽  
Chemotherapy Resistance ◽  
Germ Cell Tumors ◽  
Late Relapse ◽  
Malignant Neoplasms ◽  
Second Malignant Neoplasms ◽  
Near Term

Our knowledge about the management of men with germ cell tumors (GCTs) and its tumor biology continues to evolve. Vascular disease, metabolic syndrome, second malignant neoplasms, and hypogonadism occur after treatment for GCTs and the latency pattern resembles that seen in patients treated for Hodgkin lymphoma. Patients receiving treatment for GCTs should be informed not only of the near-term toxicity (experienced during or shortly after administration), but also the delayed and late effects of chemotherapy and the need for lifelong surveillance for all late outcomes, including late relapse. Recent data suggest that the treatment outcome of patients with intermediate-risk, poor-risk, and relapsed GCTs can be improved through multicenter trials that include the general oncology community. Finally, GCTs are a malignancy of primordial germ cells. Programmed differentiation is clinically evident in vivo and probably related to chemotherapy resistance. This biology has much clinical relevance, some of which is already in use.

Late Relapses of Germ Cell Malignancies: Incidence, Management, and Prognosis

2006 ◽  
Vol 24 (35) ◽  
pp. 5503-5511 ◽  
Author(s):  
Jan Oldenburg ◽  
Jarad M. Martin ◽  
Sophie D. Fosså
Keyword(s):  
Germ Cell ◽  
Initial Treatment ◽  
Relevant Literature ◽  
Tumor Biology ◽  
Germ Cell Tumors ◽  
High Volume ◽  
Salvage Chemotherapy ◽  
Pooled Analysis ◽  
Late Relapse ◽  
Cancer Specific Survival

Late relapses of malignant germ cell tumors (MGCTs) are rare and occur, by definition, 2 years or later after successful treatment. They represent a major challenge of today's treatment of MGCTs. Because of the rarity and heterogeneity of late relapses, many aspects of their main characteristics remain obscure. We present relevant literature on relapsing MGCTs to highlight the following issues: incidence, impact of initial treatment on the subsequent risk of late relapse, treatment, and survival. In a pooled analysis, the incidence is 1.4% and 3.2% in seminoma and nonseminoma patients, respectively. The predominant site of relapse is the retroperitoneal space in both histologic types. The initial treatment appears to be important for the risk and localization of late relapses. The treatment of late relapses should be based on a representative presalvage biopsy and includes radical surgery and salvage chemotherapy in most cases. Five-year cancer-specific survival is above 50% in the recent large series and reaches 100% in case of single-site teratoma. Diagnosis and treatment of late-relapsing MGCT patients is challenging and should be performed in experienced centers only. Referral of late-relapsing patients to high-volume institutions ensures the best chances of cure and enables increasing understanding of tumor biology and the clinical course of these patients.

scholarly journals Risk of second malignant neoplasms in women and girls with germ cell tumors

2017 ◽  
Vol 28 (2) ◽  
pp. 329-332 ◽  
Author(s):  
Z. Liao ◽  
M.C. Rodrigues ◽  
J.N. Poynter ◽  
J.F. Amatruda ◽  
C. Rodriguez-Galindo ◽  
...  
Keyword(s):  
Germ Cell ◽  
Germ Cell Tumors ◽  
Malignant Neoplasms ◽  
Second Malignant Neoplasms ◽  
Women And Girls

scholarly journals Elucidating human male germ cell development by studying germ cell cancer

Reproduction ◽  
2016 ◽  
Vol 152 (4) ◽  
pp. R101-R113 ◽  
Author(s):  
Daniel Nettersheim ◽  
Sina Jostes ◽  
Simon Schneider ◽  
Hubert Schorle
Keyword(s):  
Germ Cell ◽  
Regulatory Networks ◽  
Primordial Germ Cells ◽  
Cell Cancer ◽  
Tumor Biology ◽  
Germ Cell Tumors ◽  
Cell Development ◽  
Dna Hypomethylation ◽  
Pluripotent Cells ◽  
Germ Cell Development

Human germ cell development is regulated in a spatio-temporal manner by complex regulatory networks. Here, we summarize results obtained in germ cell tumors and respective cell lines and try to pinpoint similarities to normal germ cell development. This comparison allows speculating about the critical and error-prone mechanisms, which when disturbed, lead to the development of germ cell tumors. Short after specification, primordial germ cells express markers of pluripotency, which, in humans, persists up to the stage of fetal/infantile spermatogonia. Aside from the rare spermatocytic tumors, virtually all seminomas and embryonal carcinomas express markers of pluripotency and show signs of pluripotency or totipotency. Therefore, it appears that proper handling of the pluripotency program appears to be the most critical step in germ cell development in terms of tumor biology. Furthermore, data from mice reveal that germline cells display an epigenetic signature, which is highly similar to pluripotent cells. This signature (poised histone code, DNA hypomethylation) is required for the rapid induction of toti- and pluripotency upon fertilization. We propose that adult spermatogonial cells, when exposed to endocrine disruptors or epigenetic active substances, are prone to reinitiate the pluripotency program, giving rise to a germ cell tumor. The fact that pluripotent cells can be derived from adult murine and human testicular cells further corroborates this idea.

Biology and Genetics of Adult Male Germ Cell Tumors

2006 ◽  
Vol 24 (35) ◽  
pp. 5512-5518 ◽  
Author(s):  
Jane Houldsworth ◽  
James E. Korkola ◽  
George J. Bosl ◽  
R. S. K. Chaganti
Keyword(s):  
Germ Cell ◽  
Adult Male ◽  
Chemotherapy Resistance ◽  
Germ Cell Tumors ◽  
Embryonic Stem ◽  
High Sensitivity ◽  
Male Germ Cell ◽  
Lineage Differentiation ◽  
Genome Analyses

Adult male germ cell tumors (GCTs) arise by transformation of totipotent germ cells. They have the unique potential to activate molecular pathways, in part mimicking those occurring during gametogenesis and normal human development, as evidenced by the array of histopathologies observed in vivo. Recent expression profiling studies of GCTs along with advances in embryonic stem-cell research have contributed to our understanding of the underlying biology of the disease. Gain of the short arm of chromosome 12 detected in almost all adult GCTs appears to be multifunctional in germ cell tumorigenesis on the basis of the observed overexpression of genes mapped to this region involved in maintenance of pluripotency and oncogenesis. Expression signatures associated with the different histopathologies have yielded clues as to the functional mechanisms involved in GCT invasion, loss of pluripotency, and lineage differentiation. Genomic and epigenomic abnormalities that contribute to or cause these events have been identified by traditional genome analyses and continue to be revealed as genome-scanning technologies develop. Given the high sensitivity of most GCTs to cisplatin-based treatment, these tumors serve as an excellent model system for the identification of factors associated with drug resistance, including differentiation status and acquisition of genomic alterations. Overall, adult male GCTs provide a unique opportunity for the examination of functional links between transformation and pluripotency, genomic and epigenomic abnormalities and lineage differentiation, and the identification of genetic features associated with chemotherapy resistance.

Recent Advances in New Discovered Molecular Targets in Testicular Germ Cell Tumors

2018 ◽  
Vol 25 (5) ◽  
pp. 575-583 ◽  
Author(s):  
Paolo Chieffi
Keyword(s):  
Germ Cell ◽  
Primordial Germ Cells ◽  
Germ Cell Tumors ◽  
Molecular Targets ◽  
Testicular Germ Cell Tumor ◽  
Research Literature ◽  
Testicular Germ Cell ◽  
Solid Malignancy ◽  
Bibliographic Data ◽  
New Biomarkers

Background: Testicular germ cell tumor (TGCT) is the most common solid malignancy occurring in young men between 20 and 34 years of age, and its incidence has increased significantly over the last decades. TGCTs can be subdivided into seminoma and nonseminoma germ cell tumors (NSGCTs), which includes yolk sac tumor, choriocarcinoma, embryonal cell carcinoma, and teratoma. Seminomas and NSGCTs present significant differences in therapy, prognosis, and both show characteristics of the Primordial Germ Cells (PGCs). Methods: I undertook a search of bibliographic data from peer-reviewed research literature. Results: Seventy papers were included in the mini-review showing that a large number of new biomarkers have given further advantages to discriminate the different histotypes and could represent useful novel molecular targets for anticancer strategies. Conclusion: A deeper understanding of the pathogenesis of TGCTs is likely to significantly improve not only our knowledge on stem cells and oncogenesis but also the disease management with more selective tumor treatment.

scholarly journals TCam-2 Cells Deficient for SOX2 and FOXA2 Are Blocked in Differentiation and Maintain a Seminoma-Like Cell Fate In Vivo

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 728 ◽  
Author(s):  
Daniel Nettersheim ◽  
Saskia Vadder ◽  
Sina Jostes ◽  
Alena Heimsoeth ◽  
Hubert Schorle
Keyword(s):  
Cell Fate ◽  
Primordial Germ Cells ◽  
Germ Cell Tumors ◽  
Embryonic Stem ◽  
Bmp Signaling ◽  
Stem Cell Population ◽  
Testicular Germ Cell ◽  
Key Factor ◽  
Pioneer Factor

Testicular germ cell tumors (GCTs) are very common in young men and can be stratified into seminomas and non-seminomas. While seminomas share a similar gene expression and epigenetic profile with primordial germ cells, the stem cell population of the non-seminomas, the embryonal carcinoma (EC), resembles malignant embryonic stem cells. Thus, ECs are able to differentiate into cells of all three germ layers (teratomas) and even extra-embryonic-tissue-like cells (yolk-sac tumor, choriocarcinoma). In the last years, we demonstrated that the cellular microenvironment considerably influences the plasticity of seminomas (TCam-2 cells). Upon a microenvironment-triggered inhibition of the BMP signaling pathway in vivo (murine flank or brain), seminomatous TCam-2 cells reprogram to an EC-like cell fate. We identified SOX2 as a key factor activated upon BMP inhibition mediating the reprogramming process by regulating pluripotency, reprogramming and epigenetic factors. Indeed, CRISPR/Cas9 SOX2-deleted TCam-2 cells were able to maintain a seminoma-cell fate in vivo for about six weeks, but after six weeks in vivo still small sub-populations initiated differentiation. Closer analyses of these differentiated clusters suggested that the pioneer factor FOXA2 might be the driving force behind this induction of differentiation, since many FOXA2 interacting genes and differentiation factors like AFP, EOMES, CDX1, ALB, HAND1, DKK, DLK1, MSX1 and PITX2 were upregulated. In this study, we generated TCam-2 cells double-deficient for SOX2 and FOXA2 using the CRISPR/Cas9 technique and xenografted those cells into the flank of nude mice. Upon loss of SOX2 and FOXA2, TCam-2 maintained a seminoma cell fate for at least twelve weeks, demonstrating that both factors are key players in the reprogramming to an EC-like cell fate. Therefore, our study adds an important piece to the puzzle of GCT development and plasticity, providing interesting insights in what can be expected in a patient, when GCT cells are confronted with different microenvironments.

scholarly journals Late and Rapid Relapse in Mediastinum from Testicular Germ Cell Tumor Stage I Over 13 Years after Surgery

2019 ◽  
Vol 12 (2) ◽  
pp. 500-505
Author(s):  
Toshirou Fukushima ◽  
Takuro Noguchi ◽  
Takashi Kobayashi ◽  
Nodoka Sekiguchi ◽  
Takesumi Ozawa ◽  
...  
Keyword(s):  
Germ Cell ◽  
Mediastinal Lymph Node ◽  
Relevant Literature ◽  
Germ Cell Tumors ◽  
Stage I ◽  
Careful Examination ◽  
Late Relapse ◽  
Testicular Germ Cell Tumors ◽  
Testicular Germ Cell ◽  
Testicular Seminoma

Patients with stage I testicular germ cell tumors have a long life expectancy, but the tumors have a potential to relapse after treatment. Although relapse is observed within a few years in most cases, late relapse over 10 years after initial treatment has also been reported in patients with stage I testicular germ cell tumors. We encountered a case of testicular seminoma that developed mediastinal lymph node metastasis 13 years after radical surgery for the primary tumor. The relapsed disease progressed rapidly and the patient died within 1 month due to respiratory failure without any chance for therapy. On postmortem examination, the thoracic lesions were pathologically confirmed to be metastases from the testicular seminoma with yolk sac tumor. Here, we report the clinical course and a review of the relevant literature. Based on our experience, we emphasize long-term follow-up and/or careful examination in patients with stage I testicular germ cell tumors.

PRODUCTION OF ALPHA-FETOPROTEIN BY HUMAN GERM CELL TUMORS IN VIVO AND IN VITRO

1987 ◽  
Vol 37 (8) ◽  
pp. 1263-1277 ◽  
Author(s):  
Teiichi Motoyama ◽  
Hidenobu Watanabe ◽  
Takahiko Yamamoto ◽  
Morimasa Sekiguchi
Keyword(s):  
Germ Cell ◽  
Germ Cell Tumors ◽  
Alpha Fetoprotein

Late Relapse of Testicular Germ Cell Tumors

2015 ◽  
Vol 42 (3) ◽  
pp. 359-368 ◽  
Author(s):  
Matthew J. O’Shaughnessy ◽  
Darren R. Feldman ◽  
Brett S. Carver ◽  
Joel Sheinfeld
Keyword(s):  
Germ Cell ◽  
Germ Cell Tumors ◽  
Late Relapse ◽  
Testicular Germ Cell Tumors ◽  
Testicular Germ Cell

Aggressive surgical management of germ cell tumors with somatic-type malignancy: Pathologic features, prognostic factors, and survival outcomes.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4554-4554
Author(s):  
Kevin R Rice ◽  
Martin J Magers ◽  
Stephen Beck ◽  
Lawrence H. Einhorn ◽  
Thomas M. Ulbright ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Germ Cell ◽  
Germ Cell Tumors ◽  
Tumor Grade ◽  
Late Relapse ◽  
Testis Cancer ◽  
Risk Category ◽  
Delayed Presentation ◽  
Primary Tumor Site ◽  
Pathologic Features

4554 Background: Germ cell tumors (GCT) with somatic-type malignancy (SM) are rare occurring in approximately 3-8% of GCT cases. Prognostic factors and optimal management remain poorly-defined. Methods: The Indiana University (IU) testis cancer database was queried from 1979 to 2011 for patients demonstrating atypical histology at orchiectomy or subsequent resection of metastatic disease. Patients with transformation to PNET only were excluded due to distinct management. Chart review, pathologic review, and survival analysis were performed. Results: 122 patients met study inclusion criteria. Primary tumor site was testis in 112, retroperitoneum in 8, groin in 1, and pineal gland in 1. The most common SM histologies were sarcoma (71) and carcinoma (32). At GCT diagnosis, 24, 44, 45 patients had stage I, II, and III disease, respectively. Stage was unknown in 9. Median time from GCT diagnosis to SM was 13 months (Range, 0-397). This interval was longest for carcinomas (94.5 months) and sarcomatoid yolk sac tumors (113 months). Only 11 of 83 patients (13.3%) receiving cisplatin-based chemotherapy for measurable disease demonstrated an initial complete response. First resection at IU was reoperative in 45 patients (36.9%). 69 patients (56.6%) required extirpation of abdominal viscera/vascular structures or distant metastases. At a median follow-up of 71 months, the 5-year cancer specific survival (CSS) was 63%. Predictors of poorer CSS included SM diagnosed at late relapse (p = 0.014), referral to IU for reoperative RPLND (p = 0.022), and tumor grade (p = 0.043). SM histology subtype, stage, risk category, and number of resections for SM were not predictive of CSS. Conclusions: GCT with SM is associated with poorer CSS than traditional GCT. Established prognostic factors for GCT lose their predictive value in the setting of SM. SM can occur at any point in the course of GCT, but has a propensity for delayed presentation with later onset being associated with poorer CSS. Aggressive and serial surgical resections are often necessary to optimize CSS. Tumor grade is an important prognostic factor, particularly in sarcoma cases.

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