Malignant Testicular Germ Cell Tumors Research Articles

SMARCB1-Deficient Skull Base Chondrosarcoma with 12p Duplication Presenting as Somatic-Type Malignancy Arising from Metastatic Seminoma

Somatic-type malignancy (STM) can occur infrequently within a primary or metastatic testicular germ cell tumor (TGCT) and is associated with dismal prognosis and survival. STM with chondrosarcomatous features is exceedingly rare and head and neck involvement has not been previously documented. A 39-year-old white man presented with nasal obstruction and epistaxis. Imaging disclosed a 6.9-cm expansile tumor involving the nasal cavity and skull base with intraorbital and intracranial extension. The histopathologic properties of the tumor were compatible with chondrosarcoma, grade II-III. Immunohistochemically, malignant cells were strongly and diffusely positive for S100 and epithelial markers, and showed loss of SMARCB1 expression. IDH1/2 mutations were not detected. Following whole-body PET scan, a 7.0-cm left testicular mass was discovered and diagnosed as seminoma with syncytiotrophoblastic cells, stage pT3NXM1b. Extensive retroperitoneal, mediastinal, and supraclavicular lymphadenopathy was also noticed. Histopathologic examination of the left supraclavicular lymph node revealed metastatic seminoma. By FISH, most metastatic nodal seminoma cells harbored 1 to 4 copies of isochromosome 12p, while the chondrosarcoma featured duplication of 12p. Presence of a malignant TGCT with disseminated supradiaphragmatic lymphadenopathy, the unique immunophenotypic properties of the skull-based chondrosarcoma and lack of IDH1/2 aberrations with gain of 12p strongly support the diagnosis of STM chondrosarcoma arising from metastatic TGCT. The patient did not respond to chemotherapy and succumbed three months after diagnosis. Although exceedingly uncommon, metastasis to the head and neck may occur in patients with TGCT. This case of STM chondrosarcoma demonstrated divergent immunophenotypic and molecular characteristics compared to “typical” examples of head and neck chondrosarcoma. High index of suspicion is advised regarding the diagnosis of lesions that present with otherwise typical histomorphology but unexpected immunohistochemical or molecular features.

Translationeel onderzoek naar testiculaire kiemceltumoren

AbstractTesticular germ cell tumors are the most common malignancy in men aged 14 to 44 years. Although exceptional cisplatin sensitivity results in cure rates of > 90%, resistance can occur for which there are currently no alternative treatment options. Translational research in recent years has led to various breakthroughs in detection and classification of these tumors. The identification of miRNA-371 expression as a marker of malignant testicular germ cell tumors (with the exception of teratomas) enables significantly more sensitive and specific detection of these cancers in various clinical contexts (primary tumor, residual disease, relapse etc.). Moreover, the identification of several genetic aberrations that are associated with treatment resistance and poor outcome, such as TP53 mutations or copy number gain on chromosome 3p, underlines the necessity of genetic screening for improved risk classification of testicular cancer patients.

Targeting Cancer Stem Cells with Differentiation Agents as an Alternative to Genotoxic Chemotherapy for the Treatment of Malignant Testicular Germ Cell Tumors.

Simple SummaryTesticular germ cell tumors (TGCTs) are the most common solid malignancy in young men. Fortunately, these tumors are highly curable with conventional genotoxic chemotherapy. However, because these chemotherapeutics have significant short- and long-term side effects, less toxic treatment options are desired. We report that thioridazine, an FDA-approved antipsychotic, differentiates embryonal carcinoma (EC) cells, the cancer stem cells of many malignant TGCTs, and suppresses their tumor propagating activity. Additionally, thioridazine treatment of mice with EC-containing neoplasms extends survival relative to untreated control mice. These findings identify thioridazine as a promising alternative or adjuvant to chemotherapy for the treatment of TGCTs.Testicular germ cell tumors (TGCTs) are exceptionally sensitive to genotoxic chemotherapy, resulting in a high cure rate for the young men presenting with these malignancies. However, this treatment is associated with significant toxicity, and a subset of malignant TGCTs demonstrate chemoresistance. Mixed nonseminomas often contain pluripotent embryonal carcinoma (EC) cells, the cancer stem cells (CSCs) of these tumors. We hypothesized that differentiation therapy, a treatment strategy which aims to induce differentiation of tumor-propagating CSCs to slow tumor growth, could effectively treat mixed nonseminomas without significant toxicity. The FDA-approved antipsychotic thioridazine and the agricultural antibiotic salinomycin are two drugs previously found to selectively target CSCs, and here we report that these agents differentiate EC cells in vitro and greatly reduce their tumorigenic potential in vivo. Using a novel transformed induced pluripotent stem cell allograft model and a human xenograft model, we show that thioridazine extends the survival of tumor-bearing mice and can reduce the number of pluripotent EC cells within tumors. These results suggest that thioridazine could be repurposed as an alternative TGCT treatment that avoids the toxicity of conventional chemotherapeutics.

A Genetically Engineered Mouse Model of Malignant Testicular Germ Cell Tumors.

Testicular germ cell tumors (TGCTs) are among the most curable solid cancers and are typically highly responsive to conventional DNA-damaging chemotherapies, even in patients with metastatic disease. It has therefore been of great interest to understand the basis for the unique chemosensitivity of these cancers, which is linked to the DNA damage sensitivity of their cancer stem cells. TGCTs have been difficult to study in the mouse, however, since most of the existing mouse models develop benign teratomas that are unlike the malignant TGCTs that afflict most testicular cancer patients. We describe here methods for generating a TGCT mouse model that closely resembles the malignant, metastatic disease observed in men with testicular cancer, and additionally include methods for analyzing the cancer stems cells and responses to chemotherapeutics in these murine TGCTs.

Testis-preserving strategies in testicular germ cell tumors and germ cell neoplasia in situ.

Testicular germ cell tumors (TGCT) are rare malignancies which affect young adults and adolescents between the ages of 15 and 40 years. In suspected malignant TGCT, the treatment of choice is radical orchiectomy. However, in specific cases this routine surgical approach has been challenged in favor of an organ-preserving approach with comparable oncological outcome. Thus, testis-preserving strategies should be considered in unilateral or bilateral synchronous or metachronous TGCT as well as incidentally found small testicular masses, which are mostly benign lesions including Sertoli cell tumors, Leydig cell tumors, adenomatoid tumors or epidermoid cysts. In case of a testis-preserving surgery, adjuvant postoperative radiation therapy (20 Gy) is recommended. The rational for this approach is that the remaining parenchyma harbors germ cell neoplasia in situ (GCNIS), which might lead to locally recurrent TGCT in 50% in the next following 5 years. However, testicular radiotherapy might result in infertility and 'Sertoli-cell only' syndrome because of radiation-induced destruction of germ cells as well as Leydig cell insufficiency in 20% of all patients leading to life-long androgen substitution. Therefore, radiation therapy should be delay or sperm banking be should performed in fertile patients wish to have children. This review provides an overview on literature regarding testis-preserving strategies in TGCT as well as GCNIS.

Knowledge and early detection of testicular germ cell cancer among adolescents and young adults

Malignant testicular germ cell tumors are the most common tumor disease in young men, affecting not only the period of his reproductive phase but also creating acomplex life situation. Therapy includes the risk of development of second neoplasia and sequelae. However, particularly in this age group, knowledge about this disease and risk factors is sparse, and preventive examinations are not available or are not or insufficiently used. In order to evaluate the state of knowledge on testicular tumors in adolescents, aknowledge survey was conducted at 6high schools in Hamburg from January to April 2019 among pupils of grades 11 and 12. This was carried out with aquestionnaire comprising 15items, which was analyzed and also evaluated on agender-specific basis. Only fully completed questionnaires were considered. The overall proportion of correctly answered questions was 60.04%. Broken down by gender, the proportion was 60.18% for female pupils and 59.14% for male pupils, while the gender ratio was 52.2 and 47.8% for female pupils. Special questions on testicular tumors were answered correctly by 59.71% of the female students and 54.8% of the male students, while general questions on the structure and function of the male sexual organs were answered 4.51% better by the male students with 64.9%. These were statistically significant in both cases. The survey shows agender-specific knowledge deficit on testicular tumors, which is more pronounced among boys. As intensified knowledge transfer on this topic alone is insufficient, apreventive examination should be established especially for boys. This would enable individual, risk-commensurate and needs-adapted monitoring and early detection of testicular tumor disease, but also of other health issues in male adolescents.

Cost Analysis of Noninvasive Blood-Based MicroRNA Testing Versus CT Scans for Follow-up in Patients With Testicular Germ-Cell Tumors.

Our group has developed a noninvasive blood-based microRNA (miRNA) test for improving diagnosis, disease monitoring, and relapse detection in malignant testicular germ-cell tumors (TGCTs). Performance analysis suggests the test is likely to have comparable sensitivity and specificity in detecting TGCT as computed tomography (CT), thus reducing the need for serial CT scans for follow-up monitoring, with associated reductions in cumulative radiation burden and second cancer risk. To facilitate clinical adoption, we undertook a cost analysis to identify the budget impact of replacing CT scans with miRNA testing within health care systems. The TGCT aftercare pathway was mapped out using National Comprehensive Cancer Network guidelines. A Markov model was built to simulate the impact of the miRNA test on TGCT aftercare costs. Incidence, treatment probabilities, relapse rate, and death rate data were collected from published studies to populate the model. Applying our model to the US health care system, the miRNA test has the potential to save up to $69 million per year in aftercare expenses related to TGCT treatment, with exact savings depending on the adoption rate and test price. This analysis demonstrates the potential positive budget impact of adopting miRNA testing in place of CT scans in the clinical management of TGCTs.

METASTATIC CARDIAC TUMORS: LITERATURE REVIEW AND OWN OBSERVATION OF TESTICULAR TUMOR METASTASIS IN THE RIGHT VENTRICLE OF THE HEART

Tumors of the heart are uncommon and usually benign (in 93% cases myxomas are observed). More often secondary, metastatic tumors are detected in the heart, as a rule, at pronounced progression of the malignant neoplasm with multiple lesions of other internal organs (lung, pleura, liver, etc.). Literature review on cardiac metastases of different tumors is given. Own observation of a young man with rare single metastasis of malignant testicular germ cell tumor with predominance of embryonic carcinoma in the right ventricle of the heart is presented; the primary tumor was detected after metastasis revealing. The diagnostic algorithm using routine histological study supplemented with immunohistochemistry, including detection of cytokeratin pan, cytokeratin5/6, cytokeratin7, CD30, OCT4, TTF-1, hCG, and AFP markers expression, is described.

A Clinicopathologic and Molecular Analysis of 34 Mediastinal Germ Cell Tumors Suggesting Different Modes of Teratoma Development.

Mediastinal teratomas are enigmatic; those in children and women are almost invariably benign but in men they may be benign or malignant. There are few data on the chromosome 12p status of mediastinal germ cell tumors (GCT), whereas increased 12p copy number is virtually uniform in malignant testicular GCTs. We therefore studied chromosome 12p copy number in 34 diverse mediastinal GCTs and correlated the results with morphology and follow-up to gain insight into possible pathogenesis. Four prepubertal (below 12 y) children (3 females and 1 male), 7 postpubertal females (14 to 52 y) and 6 postpubertal males (12 to 40 y old) had pure, previously untreated teratomas; 15 were mature and 2 had low-grade immaturity. All lacked 12p copy number increase and cytologic atypia, and most (14/17) showed organoid morphology. On follow-up of 16, 1 died of postoperative complications and the remaining 15 were disease free (1 to 119 mo, mean: 39 mo). Eight postpubertal males (19 to 44 y old) had pure teratomas in postchemotherapy resections; 5/8 showed 12p copy number increase. All 8 had distinct cytologic atypia, with organoid morphology in 3. On follow-up, 6 were disease free after surgical resection (1.5 to 94 mo, mean 38 mo); 1 died of disease at 14.5 months, and 1 was alive with metastases at 176 months. Two postpubertal patients, 1 male (29 y) and 1 female (31 y), had teratoma with secondary somatic-type malignancies, with positive 12p copy number increase in the former but not the latter. The man's tumor occurred after chemotherapy and was a nonorganoid teratoma with primitive neuroectodermal tumor and malignant glioma; the woman's was a previously untreated organoid teratoma with an undifferentiated carcinoma component. The man died of disease (16 mo) and the woman was alive with metastases (27 mo). Seven patients had resections for mixed GCTs (4) or pure nonteratomatous tumors, all after chemotherapy; 5/7 had positive 12p copy number increase. The teratoma component of the 2 cases having one showed distinct cytologic atypia and lacked organoid morphology. On follow-up, 1 died of disease (5 mo), 2 were alive with disease (1, 1.5 mo), 3 were disease free (1 to 43 mo; mean: 18 mo), and 1 was alive with unknown status (31 mo). Our results support that mediastinal teratomas likely develop from 2 separate pathways. Those in children, women and some men arise as pure neoplasms from a nontransformed precursor cell and, therefore, lack 12p copy number increase, show no cytologic atypia, often have organoid morphology and are benign. Common 12p copy number increase, uniform atypia, infrequent organoid structures and malignant behavior support that pure teratomas after chemotherapy in postpubertal males derive from a malignantly transformed precursor cell. Interestingly, we identified organoid pancreatic differentiation only in the benign group and neuroglia more commonly in the malignant teratomas.

Malignant testicular germ cell tumors in children and adolescents: The AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) protocol

ObjectivesWe report the results of an Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) study on the treatment of testicular germ cell tumors (TGCT) with a pediatric PEB (pPEB) regimen (cisplatin 25 mg/m2 daily on days 1-4; etoposide 100 mg/m2 daily on days 1-4; bleomycin 15 mg/m2 on day 2, once per cycle). Methods and materialsMale patients under 18 years old with malignant TGCT were enrolled for a second national prospective protocol. All patients underwent orchiectomy at diagnosis. Those with Stage I received no chemotherapy; those with Stage II–III disease received three cycles of pPEB; and those with Stage IV received four cycles. After chemotherapy, resection of radiologically-evident residual disease was recommended. The main study end-points were overall survival and relapse-free survival. ResultsNinety-nine boys from 0.5 to 17.8 years old (median 15.4 years) were evaluable, and staged as follows: 58 Stage I (59%), 7 Stage II (7%), 14 Stage III (14%), and 20 Stage IV (20%). With a median follow-up of 59 months (range 4-165 months), 5-year relapse-free survival (95% CI) was 73% (65%-83%) for the whole sample, 65% (53%-79%) for Stage I patients, and 86% (75%-98%) for Stage II-IV patients. Five-year overall survival (95% CI) was 99% (97%-100%). ConclusionsWe confirmed a good prognosis for malignant TGCT in children and adolescents. Reducing the number of chemotherapy cycles for Stage II-III disease does not seem to negatively affect survival outcomes.

C-MET receptor as potential biomarker and target molecule for malignant testicular germ cell tumors.

Type II testicular germ cell tumors (TGCTs) represent the most frequent malignancy in Caucasian males (20–40 years). Even if diagnosed with disseminated disease, >80% of patients are cured; however, a small percentage of cases progress and result in death. It is commonly accepted that these cancers arise from a disturbed testicular embryonic niche that leads to the block of gonocyte differentiation. The subsequent development of the invasive seminomas and non-seminomas is due to a combination of genetic, epigenetic and microenvironment-based alterations (genvironment). Hepatocyte growth factor (HGF) is present in the testicular microenvironment, together with its receptor c-MET, from early embryonic development to an adult stage. In addition, c-MET is a well-known proto-oncogene involved in the onset and progression of various human cancers. Herein, we have investigated the expression and availability of HGF and c-MET in TCam-2, NCCIT and NT2D1 cells, which are type II (T)GCT representative cell lines, and the effect of c-MET activation/repression on the regulation of cancerous biological processes. We found that NT2D1 cells increase their proliferation, polarized migration, and invasion in response to HGF administration. NCCIT cells respond to HGF stimulation only partially, whereas TCam-2 cells do not respond to HGF, at least according to the investigated parameters. Interestingly, the immunohistochemical study of c-MET distribution in TGCTs confirm its presence in both seminoma and non-seminoma lesions with different patterns. Notably, we found the highest c-MET immunoreactivity in the epithelial elements of the various components of TGCTs: teratoma, yolk sac tumor and choriocarcinoma.

Protein expression of the transcription factors DMRT1, TCLF5, and OCT4 in selected germ cell neoplasms of the testis

In the present study, we investigated protein expression of the transcription factors mammalian doublesex and mab-3 related transcription factor 1 (DMRT1), basic helix-loop-helix transcription factor-like 5 (TCLF5), and octamer-binding transcription factor 4 (OCT4) in normal human spermatogenesis, testicular mixed germ cell-sex cord stromal tumor (MGC-SCST), spermatocytic tumor, and seminoma. In normal human spermatogenesis, DMRT1 is expressed in the nuclei of spermatogonia but not in those of more mature germ cells. By way of contrast, TCLF5 is expressed in the nuclei of some clusters of primary spermatocytes that have entered meiosis 1, in secondary spermatocytes, and in round (early) spermatids in the seminiferous tubules of adults during the reproductive years. OCT4 is expressed in primordial germ cells but not in the seminiferous tubules of the normal adult testis during the reproductive years. DMRT1 is expressed in the germ cells of both testicular MGC-SCST and spermatocytic tumor, whereas TCLF5 is not expressed in either neoplasm. These low-grade neoplasms, however, differ histologically in that all the germ cell nuclei of testicular MGC-SCST resemble spermatogonia, whereas in spermatocytic tumor, the nuclei of the medium-sized and large cells resemble those of primary spermatocytes. Both neoplasms lack expression of OCT4. By way of contrast, in seminoma, a fully malignant testicular germ cell tumor, the germ cell nuclei express OCT4 but do not express either DMRT1 or TCLF5.

The rapidly changing incidence of gonadal germ cell tumours

Background: Over the past 30 years the incidence of malignant testicular germ cell tumours has increased significantly.1 This has not been observed in some studies of ovarian germ cell tumours.2 The explanation for these changes remains uncertain.

Malignant testicular germ cell tumors in postpubertal individuals with androgen insensitivity: prevalence, pathology and relevance of single nucleotide polymorphism-based susceptibility profiling.

What is the prevalence of malignant testicular germ cell tumors (TGCT) and its precursors, (pre-) germ cell neoplasia in situ (GCNIS), in late teenagers and adults who have androgen insensitivity syndrome (AIS) and the impact of an individual's genetic susceptibility to development of TGCT? No GCNIS or TGCT was diagnosed, but pre-GCNIS was identified in 14 and 10% of complete and partial AIS patients, respectively, and was associated with a higher genetic susceptibility score (GSS), with special attention for KITLG (rs995030) and ATFZIP (rs2900333). Many adult women with AIS decline prophylactic gonadectomy, while data regarding the incidence, pathophysiology and outcomes of TGCT in postpubertal individuals with AIS are lacking. The relevance of genetic factors, such as single nucleotide polymorphisms (SNPs), in predisposing AIS individuals to TGCT is unknown. This multicenter collaborative study on prophylactically removed gonadal tissue was conducted in a pathology lab specialized in germ cell tumor biology. Material from 52 postpubertal individuals with molecularly confirmed AIS (97 gonadal samples) was included; the median age at surgery was 17.5 (14-54) years. Immunohistochemical studies and high-throughput profiling of 14 TGCT-associated SNPs were performed. The main outcome measures were the prevalence of pre-GCNIS, GCNIS and TGCT, and its correlation with a GSS, developed based on the results of recent genome-wide association studies. The earliest recognizable change preceding GCNIS, referred to as pre-GCNIS, was present in 14% of individuals with complete and 10% of those with partial AIS at a median age of 16 years. No GCNIS or invasive TGCT were found. The median GSS was significantly greater for those with, compared to those without, pre-GCNIS (P = 0.01), with an overlap between groups. Our data suggest important roles for risk alleles G at KITLG (rs995030) and C at ATFZIP (rs2900333), among the 14 studied TGCT-associated SNPs. N/A. A limited number of cases were included. Our data suggest that the prevalence of pre-GCNIS in individuals with AIS beyond puberty is around 15%. Genetic susceptibility likely contributes to pre-GCNIS development in AIS but factors related to malignant progression remain unclear. Although data in older patients remain scarce, malignant progression appears to be a rare event, although the natural history of the premalignant lesion remains unknown. Therefore, the practice of routine prophylactic gonadectomy in adults with AIS appears questionable and the patient's preference, after having been fully informed, should be decisive in this matter. This study was supported by research grants from the Research Foundation Flanders (FWO) (to M.C.), the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq G0D6713N) (to B.B.M. and M.C.) and the European Society for Pediatric Endocrinology (ESPE), granted by Novo Nordisk AB (to J.K.). There are no competing interests.

MicroRNA-199a-3p functions as tumor suppressor by regulating glucose metabolism in testicular germ cell tumors

microRNA (miR)-199a-3p serves critical roles in cancer development and progression. In order to improve knowledge of the functional mechanism of miR‑199a‑3p in testicular tumors, the present study characterized the regulation of aerobic glycolysis by miR‑199a‑3p and its impact on metabolism. Using3‑4,5‑dimethylthiazol‑2‑yl‑2,5diphenyl tetrazolium bromide, wound healing and flow cytometry assays, it was determined that overexpression of miR‑199a‑3p in Ntera‑2cells caused suppression of cell growth and migration. Further biochemical methods and high‑throughput quantitative polymerase chain reaction array of metabolic genes showed that inhibition of miR‑199a‑3p markedly elevated lactate production and12differentially expressed genes, including2upregulated and10downregulated genes, were identified following treatment with miR‑199a‑3p in Ntera‑2cells. In clinical samples, four selected genes, lactate dehydrogenaseA, monocarboxylate transporter1, phosphoglycerate kinase1 and TP53‑inducible glycolysis and apoptosis regulator, were significantly overexpressed in malignant testicular germ cell tumor, and their expression inversely correlated with the expression of miR‑199a‑3p, suggesting that these four genes may be affected by miR‑199a‑3p. Using bioinformatics analysis, the transcription factor Sp1binding site was identified in the promoter region of the four selected genes. In addition, miR‑199a‑3p was predicted to bind to conservative target sequences in the 3'‑untranslated region of Sp1mRNA, suggesting that miR-199a-3p may downregulate these four metabolic genes through Sp1. It was demonstrated the dysregulated expression and activation of miR‑199a‑3p may serve important roles in aerobic glycolysis and tumorigenesis in patients with testicular cancer. Therefore, miR-199a-3p may be a potential biomarker in the prognosis and treatment of testicular tumors.

Testicular cancer ethnic disparities in the Waikato region, New Zealand.

e18065Background: Indigenous New Zealand Maori have higher rates of malignant testicular germ cell tumours than individuals of European ancestry. Higher rates of cryptochrodism in Maori compared to...

Right Cardiac Chambers Involvement by a Malignant Testicular Germ Cell Tumor: An Imaging-pathologic Correlation

The cardiac chamber's involvement with neoplastic embolism has been rarely reported; it is mostly associated with gastric, breast, lung, liver, and prostate cancers, and usually affects the pulmonary arteries. This paper reports a case of a 31-year-old man with a malignant testicular germ cell tumor who presented with multiple episodes of pulmonary thromboembolism and died of sudden respiratory failure 1 year after the initial diagnosis. Death was attributed to massive pulmonary embolism and pulmonary infarction associated with a neoplastic thrombus that extended from the gonadal veins to pulmonary arteries. A postmortem computerized tomographic angiography and autopsy confirmed this finding.

Surveillance after initial surgery for Stage I pediatric and adolescent boys with malignant testicular germ cell tumors: Report from the Children’s Oncology Group

PurposeThe purpose of this study was to determine prognostic factors correlating with outcome in boys with Stage I malignant testicular germ cell tumors (MTGCT) initially managed with surveillance after surgical resection. MethodsBetween November 2003 and July 2011, 80 boys 0–15years with Stage I MTGCT were enrolled in Children’s Oncology Group Study AGCT0132. Those with residual or recurrent disease were treated with chemotherapy. ResultsCharacteristics include: age (65, 0–5years and 15, 11+years), pure YST (93.9%, 0–5years and 0%, 11+years); and lymphovascular invasion (LVI) (50.6% present vs. 49.4% absent). At median follow-up of 4.94years, 19 had persistent or recurrent disease, all detected by elevated AFP at a median of 87days after study enrollment. The outcome from enrollment was 4-year EFS 74% (95% CI: 63%–83%) and 4-year OS 100%. 4-year EFS was improved with younger age (<11years, 80% vs. 11+years, 48%, p<0.01); pure YST vs. mixed histology (81% vs. 45%, p<0.01), and lack of LVI (84% vs. 62%, p=0.03). ConclusionsBoys with Stage I MTGCT have excellent overall survival when treated with surgery alone. Age greater than 10years, mixed histology and presence of LVI are each associated with relapse and may allow identification of high risk boys at time of enrollment.

BMI at diagnosis and adverse outcomes among men with malignant testicular germ cell tumors.

400 Background: Previous studies evaluating the relationship between measures of anthropometry, such as body mass index (BMI), and risk of testicular cancer have been conflicting, with most finding null or inverse associations. Methods: We conducted a retrospective review of 960 germ cell tumors among patients treated at the Dana-Farber Cancer Institute (DFCI) between 1997 and 2012 with information on BMI. BMI at diagnosis, tumor characteristics, IGCCC classification, treatment, relapse and cause of death was ascertained from electronic medical record review. We divided the men and conducted the analyses separately for two groups: 1) men who presented as clinical stage 1 (CS1), and 2) men who presented with metastases or were CS1 at diagnosis and developed metastases (lifemets). We conducted logistic regression to evaluate the association between BMI and characteristics at diagnosis, and Cox proportional hazards regression to investigate the risk of relapse and testicular cancer death. Results: 65% of men (n=628) were overweight or obese at diagnosis. We did not find an association between BMI and tumor characteristics at baseline, such as histology, lymphovascular invasion, or tumor size for either group. Among CS1 patients, men who were overweight or obese had a non-statistically significant reduced risk of relapse compared to men who were normal weight (HR: 0.83, 95% CI: 0.53-1.30). Among the lifemets group, 16% of men relapsed (n=83) and 8% died of testicular cancer (n=43). Although not statistically significant, men who were overweight or obese were less likely to present with intermediate (OR = 0.77, 95 CI: 0.39-1.52) and poor (OR = 0.66, 95% CI: 0.36-1.20) rather than good risk disease when compared to men with normal BMI. After adjusted for confounding variables, BMI was not associated with risk of relapse (HR: 0.94, 95% CI: 0.59-1.51) or risk of testicular cancer death (HR: 1.00, 95% CI: 0.54-1.84) among the lifemets group. Conclusions: We did not find an association between BMI at diagnosis and tumor characteristics at baseline, or risk of relapse or testicular cancer death among men with testicular cancer.

Etiology and early pathogenesis of malignant testicular germ cell tumors: towards possibilities for preinvasive diagnosis.

Malignant testicular germ cell tumors (TGCT) are the most frequent cancers in Caucasian males (20–40 years) with an 70% increasing incidence the last 20 years, probably due to combined action of (epi)genetic and (micro)environmental factors. It is expected that TGCT have carcinoma in situ (CIS) as their common precursor, originating from an embryonic germ cell blocked in its maturation process. The overall cure rate of TGCT is more than 90%, however, men surviving TGCT can present long-term side effects of systemic cancer treatment. In contrast, men diagnosed and treated for CIS only continue to live without these long-term side effects. Therefore, early detection of CIS has great health benefits, which will require an informative screening method. This review described the etiology and early pathogenesis of TGCT, as well as the possibilities of early detection and future potential of screening men at risk for TGCT. For screening, a well-defined risk profile based on both genetic and environmental risk factors is needed. Since 2009, several genome wide association studies (GWAS) have been published, reporting on single-nucleotide polymorphisms (SNPs) with significant associations in or near the genes KITLG, SPRY4, BAK1, DMRT1, TERT, ATF7IP, HPGDS, MAD1L1, RFWD3, TEX14, and PPM1E, likely to be related to TGCT development. Prenatal, perinatal, and postnatal environmental factors also influence the onset of CIS. A noninvasive early detection method for CIS would be highly beneficial in a clinical setting, for which specific miRNA detection in semen seems to be very promising. Further research is needed to develop a well-defined TGCT risk profile, based on gene-environment interactions, combined with noninvasive detection method for CIS.