Dynamic changes in the expression of apoptosis-related genes in differentiating gonocytes and in seminomas

Apoptosis is an integral part of the spermatogenic process, necessary to maintain a proper ratio of Sertoli to germ cell numbers and provide an adequate microenvironment to germ cells. Apoptosis may also represent a protective mechanism mediating the elimination of abnormal germ cells. Extensive apoptosis occurs between the first and second postnatal weeks, at the point when gonocytes, precursors of spermatogonial stem cells, should have migrated toward the basement membrane of the tubules and differentiated into spermatogonia. The mechanisms regulating this process are not well-understood. Gonocytes undergo phases of proliferation, migration, and differentiation which occur in a timely and closely regulated manner. Gonocytes failing to migrate and differentiate properly undergo apoptosis. Inadequate gonocyte differentiation has been suggested to lead to testicular germ cell tumor （TGCT） formation. Here, we examined the expression levels of apoptosis-related genes during gonocyte differentiation by quantitative real-time polymerase chain reaction, identifying 48 pro- and anti-apoptotic genes increased by at least two-fold in rat gonocytes induced to differentiate by retinoic acid, when compared to untreated gonocytes. Further analysis of the most highly expressed genes identified the pro-apoptotic genes Gadd45a and Cycs as upregulated in differentiating gonocytes and in spermatogonia compared with gonocytes. These genes were also significantly downregulated in seminomas, the most common type of TGCT, compared with normal human testicular tissues. These results indicate that apoptosis-related genes are actively regulated during gonocyte differentiation. Moreover, the down-regulation of pro-apoptotic genes in seminomas suggests that they could represent new therapeutic targets in the treatment of TGCTs.

Identification of sumoylated targets in proliferating mouse spermatogonia and human testicular seminomas

Spermatogenesis is regulated by a complex network of posttranslation modifications.Sumoylation(a modification by small ubiquiti like modifiers,or SUMO proteins)was identified as an importa nt cellular event in d iff ere nt cell types.SUMO proteins are highly expressed in the testis,and their role during spermatogenesis has begun to be elucidated.Given the important role of sumoylation in the regulation of mitosis and cancer progress!on in other tissues,the aim of the current study was to identify the targets of SUMO in proliferating mouse spermatog onia and huma n semi noma tissues and to in itially exami ne the level of sumoylation in relation to the proliferative activity of the tissues.Using freshly purified spermatogonia and Cl8-4 spermatogonia cell line,mass spectrometry analysis identified several SUMO targets implicated into the proliferation of spermatogonia(such as heat shock protein 60[HSP60]and prohibitin).Tissue array and western blot approaches showed that SUMO expression is a prominent feature of human seminomas and that the proliferative activity of the tumor tissues was positively correlated with the level of SUMO expression.Down regulation of sumoylati on with si-RNA was not sufficie nt to sign ificantly affect the proliferation of C18-4 spermatogonia;however,SUMO overexpression in creased the proliferation rate of the cells.These data suggest that cells are more sensitive to an elevated level of SUMO,and that this situation may lead to an upregulated cellular proliferation and,possibly,cancer.Mass spectrometry analysis identified around a hundred SUMO targets in seminoma samples.Notably,many of the identified proteins(such as proliferating cell nuclear antigen[PCNA],DNA topoisomerase 2-alpha[Top2A],prohibitin,14-3-3 protein,and others)were implicated in oncogenic transformation and cancer progression.

Diagnosis and treatment of primary seminoma of the prostate:A case report and review of literature

BACKGROUND Primary seminoma of the prostate(PSP)is a rare type of extragonadal germ cell tumour that is easily misdiagnosed,owing to the lack of specific clinical features.It is therefore necessary for clinicians to work toward improving the accuracy of PSP diagnosis.CASE SUMMARY A 59-year-old male patient presenting with acute urinary retention was admitted to a local hospital.A misdiagnosis of benign prostatic hyperplasia led to an improper prostatectomy.Histopathology revealed PSP invading the bladder neck and bilateral seminal vesicles.Further radiotherapy treatment for the local lesion was performed,and the patient had a disease-free survival period of 96 mo.This case was analysed along with 13 other cases of PSP identified from the literature.Only four of the cases(28.6%)were initially confirmed by prostate biopsy.In these cases,imaging examinations showed an enlarged prostate(range 6-11 cm)involving the bladder neck(13/14).Of the 14 total cases,11(78.6%)presented typical pure seminoma cell features,staining strongly positive for placental alkaline phosphatase,CD117,and OCT4.The median age at diagnosis was 51(range 27-59)years,and patients had a median progression-free survival time of 48(range 6-156)mo after treatment by cisplatin-based chemotherapy combined with surgery or radiotherapy.The remaining three were cases of mixed embryonal tumours with focal seminoma,which had clinical features similar to those of pure PSP,in addition that they also had elevated serum alpha fetoprotein,beta-human chorionic gonadotropin,and lactose dehydrogenase.CONCLUSION PSP should be considered in patients younger than 60 years with an enlarged prostate invading the bladder neck.Further prostate biopsies may aid in proper PSP diagnosis.Cisplatin-based chemotherapy is still the main primary therapy for PSP.

Clinical significance of VEGF, ER and AR expression in seminoma

To evaluate the expression of vascular endothelial growth factor (VEGF), estrogen receptor (ER) and androgen receptor (AR) in the genesis and development of seminoma. Methods: The expression of VEGF, ER and AR was assayed by means of immuno-histochemical technique in 16 cases of seminoma and 10 cases of prostatic cancer (Pca). Results: The VEGF expression positive rate was significantly higher (P<0.05) in seminoma than in Pca, being 14/16(87.5 %) and (4/10, 40%), respectively. The AR expression positive rate was lower (P>0.05) in seminoma (9/16, 56.2%) than in Pca (9/10, 90%). The ER expression was negative in all the seminoma and Pca patients. Conclusion: In seminoma, the expression of VEGF is significantly increased, which may play a role in the genesis and development of the neoplasm. (Chin J Androl 2002; 16: 349)

Gastric adenocarcinoma with features of endodermal sinus tumor

Extragonadal germ cell tumors are rare. The most common sites for EGGCTs are in midline locations such as the mediastinum, retroperitoneum and pineal gland. These tumors rarely present in the stomach. We describe here a case where a middle aged man presented with typical symptoms of gastric cancer. After extensive workup, which included blood work, CT abdomen scan, upper endoscopy, and endoscopic ultrasound, the patient was diagnosed with gastric cancer. However, due to very high blood levels of alpha-fetoprotein, the specimen was sent for special histochemical staining, which demonstrated that the tumor had features of both adenocarcinoma and endodermal sinus tumor. This is a very aggressive tumor with a very poor prognosis.

MicroRNA-371a-3p as a blood-based biomarker in testis cancer

MicroRNAs(miRNAs)are small noncoding RNAs involved in the regulation of mRNA transcription and translation,and possess all desirable features of an ideal tumor marker.Of almost 31 different miRNA clusters identified in germ cell tumors(GCTs),miR-371a-3p has shown exceptionally high sensitivity and specificity for both seminomatous and nonseminomatous GCTs.It is easily obtainable and correlates well with tumor burden.Recent multiinstitutional prospective studies have shown promising test characteristics for miR-371a-3p as a diagnostic blood-based biomarker for GCT prior to orchiectomy including 80%e100%sensitivity and 90%e100%specificity.This accuracy may address other unmet needs in the management of patients with GCT.Early studies have suggested the utility of miR-371a-3p in detecting occult nodal metastasis in high-risk clinical stage I and early stage II disease.Ongoing clinical trials including SWOG 1823 and AGCT1531 are specifically designed to confirm the utility of miR-371a-3p in clinical stage I GCT.Despite its strong association with viable GCT after treatment with chemotherapy,miR-371a-3p does not seem to accurately predict the presence of teratoma in residual lesions.Also,standardization of extraction and interpretation methods is a necessary step to assure uniform results across different institutions.

Primary Embryonal Lung Carcinoma and Testicular Seminoma in the Same Patient Ten-Years Later: Case-Report and Literature Review

Primary germ cell tumors of lung are extremely rare. The prognosis is usually poor, with various symptoms seriously affecting quality of life. In this paper we describe the unique case of a patient affected by an embryonal carcinoma of lung and a testicular seminoma after ten years. We also report literature about pulmonary extragonadal germ cell tumors.

Late recurrence of localized pure seminoma in prostate gland:A case report

BACKGROUND Late relapses of early-stage germ cell tumors are rare.Most patients(-85%)with stage I seminoma are cured by radical orchiectomy.The detection of late relapse is challenging given the relative rarity of this phenomenon,and the fact that patients who have completed surveillance are usually not undergoing regular oncologic workup nor imaging.While many treatment options do exist for a patient with late relapse of seminoma,surgery is typically the mainstay as these tumors are generally thought to be more chemo-resistant.CASE SUMMARY In this article,we describe the management of a patient with an early-stage pure seminoma who was subsequently identified to have a recurrence two decades later.We provide a review of the literature not only focused on clinical factors and biology,but also the management of late recurrences specifically in pure seminoma and in prostate gland.CONCLUSION There is a paucity of data and treatment recommendations for this clinical entity,and a multidisciplinary approach emphasizing subspecialty expert consultation and patient education is imperative.

Treatment options in stage I seminoma

Seminomas are most commonly diagnosed in clinical stage I(CSI).After orchiectomy,approximately 15%of patients in this stage have subclinical metastases.Adjuvant radiotherapy(ART)delivered to the retroperitoneum and ipsilateral pelvic lymph nodes has been the mainstay of treatment for many years.Although highly efficient,with long-term cancer-specific survival(CSS)rates approaching almost 100%,ART is associated with considerable long-term consequences,particularly cardiovascular toxicity and increased risk of secondary malignancies(SMN).Therefore,active surveillance(AS)and adjuvant chemotherapy(ACT)were developed as alternative treatment options.While AS prevents patient overtreatment,it is associated with strict follow-up regimens and increased radiation exposure due to repeated imaging.Due to equivalent CSS rates to ART,and lower toxicity,one course of adjuvant carboplatin presents the cornerstone of chemotherapy for CSI patients.CSS is almost 100%for patients with CSI seminoma,regardless of the chosen treatment option.Therefore,a personalized approach in treatment selection is preferred.Currently,routine radiotherapy for CSI seminoma patients is no longer recommended.Instead,it should be reserved for patients who are unfit or unwilling for AS or ACT.Identification of prognostic factors for disease relapse allowed for the development of risk-adapted treatment strategy and stratification of patients in low-risk and high-risk groups.Although risk-adapted policy needs further validation,surveillance is currently recommended in low-risk patients,while ACT is reserved for patients with a higher risk of relapse.

Immunolocalization of Epidermal Growth Factor in Human Fetal, Adult and Cryptorchid Testes and Seminoma

EGF was localized in human fetal, adult and cryptorchid testis and seminoma using an immunohistochemical method. Leydig cells of adult testes stained intensely for EGF while those of fetal testes showed weak staining reaction. In addition, some spermatogonia and occasional peritubular myoid cells of adult testis stained positively. In cryptorchid testis, there were clusters of Leydig cells interspersed between seminiferous tubules with varying staining intensities. The number of positively stained cells in the cryptorchid testis were fewer than that in adult testes. The decrease in the number of Leydig cells producing EGF may account for the spermatogenesis arrest and infertility associated with this disorder.Intense staining of the cytoplasm of seminoma cells was observed, suggesting that the high production of EGF may be related to their invasive property. In conclusion, EGF is produced by human testis and Leydig cells are the principal source of this cytokine.

Successful pregnancy in a seminoma patient after fertility preservation

The frequency of invasive cancer in young patients is increasing worldwide. For patients about to undergo a surgical procedure or to receive chemical therapy, radiation therapy, loss or impairment of fertility is a major issue. So the need for fertility protection and preservation became more intensity. Sperm banking is a standard accepted procedure for males to circumvent loss or damage to spermatozoa. Here we present a successful pregnancy in a testicular germ cell tumor patient following fertility preservation.

Acute inferior myocardial infarction in a young man with testicular seminoma:A case report

BACKGROUND Atherosclerosis represents the main cause of myocardial infarction(MI);other causes such as coronary embolism,vasospasm,coronary-dissection or drug use are much rarely encountered,but should be considered in less common clinical scenarios.In young individuals without cardiovascular risk factors,the identification of the cause of MI can sometimes be found in the medical history and previous treatments undertaken.CASE SUMMARY We present the case of a 34-year-old man presenting acute inferior ST-elevation MI without classic cardiac risk factors.Seven years ago,he suffered from orchidopexy for bilateral cryptorchidism,and was recently diagnosed with right testicular seminoma for which he had to undergo surgical resection and chemotherapy with bleomycin,etoposide and cisplatin.Shortly after the first chemotherapy treatment,namely on day five,he suffered an acute MI.Angiography revealed a mild stenotic lesion at the level of the right coronary artery with suprajacent thrombus and vasospasm,with no other significant lesions on the other coronary arteries.A conservative treatment was decided upon by the cardiac team,including dual antiplatelets therapy and anticoagulants with good further evolution.The patient continued the chemotherapy treatment according to the initial plan without other cardiovascular events.CONCLUSION In young individuals with no cardiovascular risk factors undergoing aggressive chemotherapy,an acute MI can be caused by vascular toxicity of several anticancer drugs.

Treatment and prognosis of primary mediastinal seminoma

Objective: To investigate the surgical treatment and prognosis of the primary mediastinal seminoma. Methods: Three cases with primary mediastinal seminoma from 1985 were retrospectively studied. They were male, aged 23, 36 and 32 years respectively. The primary symptoms were chest pain and coughing. The chest X-ray examination revealed solid round mass in the anterior mediastinum, with the diameters varied from 3 cm to 18 cm and a smooth clear edge. The diagnosis was not clearly in all three cases, and then operation was performed. Results: There were no operative deaths and complications. The tumor was radically removed in 2 cases and palliatively removed in 1 case. The post-operative pathological diagnosis is seminoma in all three cases. Radiotherapy were performed in 4 weeks after operation. All cases have been followed up to now, with 1 cases of death and 2 cases survival. Conclusion: Primary seminoma of the mediastinum is very rare. Operation is the main treatment for the primary mediastinal seminoma. Seminoma shows a good prognosis.

Cancer on Testicle Not Descended: Clinical and Therapeutic Aspects of 7 Cases

Objective: To study the clinics and therapeutics of testicular cancer not descended in Senegal. Patients and Methods: This is a retrospective study over a period of 15 years between January 1997 and January 2012. It focused on 07 patients. Results: The average hospital incidence was less than one case per year. The average age of patients was 30.7 years with a median of 28 (range, 21 years and 38 years). The reasons for consultation were dominated by the existence of an abdominal or pelvic mass associated with an emptiness of the stock market. Orchiectomy was the main therapeutic gesture. It was performed by transperitoneal route. CT-TAP was performed in all cases and revealed a tumor independent of the liver of the spleen or kidneys, developed on an undescended testicle. Four cases of lumbar-aortic lymph node metastasis were noted. Histologically, we noted four cases of embryonic carcinoma and three cases of seminoma. Four patients died within six months postoperatively. Two in an intestinal obstruction chart, one in a peritoneal carcinomatosis chart and one patient in a pulmonary embolism chart. Two had a 4-year survival without recurrence. One patient had a 7-year survival without recurrence. At the time of the counting, these three patients were lost sight off. Conclusion: Intra-abdominal or pelvic development of testicular cancer is rare. It constitutes a major subsequent risk of the undescended testicle.

Meta-Analysis to Determine the Diagnostic Value of 2-¹⁸Fluoro-2-Deoxy-D-Glucose Positron Emission Tomography in Assessing Residual Tumors after Systemic Therapy for Metastatic Seminoma

Background: A meta-analysis was performed to determine the value of 2-18fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) for assessing viable tumor residuals after chemotherapy in patients with pure seminoma. Materials and methods: This review included five studies published between 1999 and 2010 with a total of 130 patients who underwent both computed tomography (CT) and FDG-PET scanning for residual tumor detection after systemic therapy. We compared the sensitivity and specificity of FDG-PET and CT (tumor size ≤ or > 3 cm) in identifying vital tumor tissue. Results: On the average, FDG-PET had higher specificity (92% vs. 59%) and sensitivity (72% vs. 63%) as well as a higher positive predictive value (PPV) than the solely size-based CT assessment of residual tumors (70% vs. 28%). PEt also tended to have a higher negative predictive value (93% vs. 86%). Conclusion: The present evaluation of currently available data indicates that FDG-PET is superior to CT in detecting viable tumor residuals after chemotherapy in patients with metastatic seminoma. Its application can thus be recommended.

Testicular Seminoma and Peritonitis about One Case at the Yalgado Ouedraogo University Hospital of Ouagadougou

Introduction: Testicular seminoma is a highly lymphophilic germ cell tumor. It is the most common germ cell tumor in young adults. We are reporting one case of testicular seminoma complicated with an acute generalized peritonitis (AGP), in order to describe the circumstances of diagnosis and discuss about treatment. Observation: It involved a 39-year-old patient, admitted for vague abdominal pains that were evolving since 72 hours with a history of right orchiectomy because of testicular seminoma in 2011. The analysis revealed a peritoneal syndrome, a right inguinal lymphadenopathy of 10 cm diameter and an empty right scrotum. The exploration revealed fistulized necrotic retro-peritoneal lymphadenopathies in the peritoneal cavity and ileal perforation on contact with these lymphadenopathies. Necrosectomy and ileal resections were performed. After the operation, the scanner revealed a conglomeration of retro-peritoneal adenomegalies extending to the right femoral region associated with bilateral pleurisy. The β-HCG and the LDH were 8000 IU/L and 24,500 IU/L, respectively. The seminoma was ranked T3N3M1. The immediate post-operative care was uneventful. The patient was lost from sight for a month and was readmitted in a context of alteration of his general condition. He died before the end of the pre-chemotherapeutic assessment. Conclusion: Scrotal mass is the usual way of revelation of testicular seminoma. In poorly followed-up cases, exceptional complications such as peritonitis may occur and are direct consequences of poor prognosis.

Supraclavicular Neck Mass as Sole Presenting Symptom for Seminoma in an Elderly Male

We report an unusual case of genitourinary malignancy in an otherwise asymptomatic elderly male, which was discovered via workup of a supraclavicular neck mass. We present his clinical workup as well as the pathological workup and how it influenced our decision-making. A review of the literature is also discussed and demonstrates how uncommon it is for seminomas to present in this manner.

Classical seminoma in a 92-year-old patient

Seminoma is a germ cell tumour which primarily affects the testes. Seminomas are treated by orchidectomy with usually excellent outcomes. We report the occurrence of a classical seminoma in a 92-year-old man,who is currently the oldest patient with this histology reported in literature. He presented with a painful,swollen testis. Scrotal ultrasound scan revealed a testicular mass. A left inguinal orchidectomy was carried out and histological examination confirmed the diagnosis of a classical seminoma. Further staging by computerised tomography revealed pulmonary lesions suspicious of metastases. The patient declined further treatment in view of his age and co-morbidities.

Programmed cell death protein 4 expression in renal cell carcinoma, penile carcinoma and testicular germ cell cancer

AIM:To investigate the expression of programmed cell death 4(Pdcd4)tumor suppressor gene in tissue specimen of renal cell carcinoma(RCC),testicular germ cell cancer and penile cancer.METHODS:Pdcd4 expression was studied using immunohistochemistry in 188 cases of RCC and 28 controls(including 9 oncocytoma);in 74 cases of penile carcinoma(including 17 metastatic tissue samples)and26 controls;in 11 cases of seminoma,in 14 cases of non-seminoma and 5 controls.RESULTS:Control tissues exhibited strong core and cytoplasmatic Pdcd4 staining.In contrast,core and cy-toplasmatic Pdcd4 levels were significantly decreased in cancer tissues.CONCLUSION:Our data support a role for Pdcd4(down-)regulation in urologic tumors.Interestingly,Pdcd4 expression seem to be a potential diagnostic marker for renal or penile tumors.

A single institution, retrospective study of treatment experience in primary mediastinal germ cell tumors： elucidating the significance of systemic chemotherapy

Background Primary malignant germ cell tumors （GCTs） of mediastinum are rare neoplasms.We introduce our institutional experience in managing patients with primary malignant GCTs of the mediastinum,focusing on the analysis of therapeutic modalities.Methods A retrospective review was done in 39 consecutive patients with mediastinal malignant GCTs treated in our institution between 1991 and 2007.Results A total of 39 patients were enrolled in this study with a median age of 27 years.The 5-year overall survival （OS） and progression-free survival （PFS） rates of the whole population were 60.2% and 57.7%,respectively.Stratified by the histology,18 patients （46.2%） had seminoma and 21 patients （53.8%） had nonseminomatous germ cell tumors （NSGCTs）.The 5-year OS rate of patients with seminoma was 87.4% as compared with 36.7% in patients with NSGCTs （P=-0.0004）.The 5-year PFS rate was also significantly higher in seminoma patients （87.4% vs.31.6%,P=-0.003）.For 19 patients with NSGCTs managed with multi-modality treatment,chemotherapy exposure appeared to impact the prognosis.The 5-year OS rate was 44.9% in patients with chemotherapy exposure as compared with 20.0% in patients without it （P=0.43）.Conclusion Our study confirmed the significance of systemic chemotherapy in the treatment of primary mediastinal GCTs.