The Application Value of Contrast-Enhanced Ultrasound in Testicular Occupied Lesions.

OBJECTIVE: To discuss the clinical application value of contrast-enhanced ultrasound (CEUS) in testicular occupied lesions. METHODS: Nine conventional-ultrasound-found testicular occupied lesions which underwent CEUS meantime were analyzed retrospectively. The CEUS perfusion pattern was compared with the surgical pathological result or follow-up findings. RESULTS: Among all the 9 testicular occupied lesions, there were 5 testicular malignant tumors, 1 testicular benign tumor, 1 testicular tuberculosis, and 2 testicular hematomas. CEUS diagnosed 6 testicular malignant tumors, 1 testicular benign tumor, and 2 testicular hematomas, and its diagnostic accuracy was about 88.9%. CONCLUSION: CEUS has high clinical application value in the differential diagnoses of benign and malignant testicular occupied lesions.

Imaging findings of ovarian dysgerminoma with emphasis on multiplicity and vascular architecture: pathogenic implications.

We report the imaging findings of three ovarian dysgerminomas that coexisted with other germ cell tumors or gonadoblastomas, focusing on the distribution of tumor nests and vascular architecture, which might provide information about the pathogenesis of dysgerminomas. In a 14-year-old female with dysgerminoma and coexisting gonadoblastomas, contrast-enhanced magnetic resonance imaging (MRI) demonstrated a solid mass in the right ovary, which presented as hyperintense lobules on diffusion-weighted imaging separated by fibrovascular septa. Some small nodules were found to exist separately from the lobules (multiplicity) and to include pathological remnants of gonadoblastoma. Large tumor vessels were present at the center of the mass (central blood vessels), which were in direct contact with the ovarian veins and radiated peripherally through the fibrovascular septa. In a 35-year-old female, a mixed germ cell tumor, which was mainly composed of dysgerminoma and yolk sac tumor foci, exhibited the same vascular architecture pattern as the first dysgerminoma on contrast-enhanced computed tomography. In a 10-year-old female with a mixed germ cell tumor, contrast-enhanced MRI revealed an enlarged left ovary, which contained a large heterogeneous mass and multiple tiny nodules (multiplicity). Microscopically, the former corresponded to a yolk sac tumor, and the latter corresponded to a dysgerminoma containing remnants of gonadoblastoma. Based on these cases, the presence of tumor nest multiplicity and central blood vessels might aid the diagnosis of dysgerminoma, and these imaging findings might be indicative of the synchronous development of multiple dysgerminomas from primordial germ cells or gonadoblastomas.

Expression of syndecan-4 and correlation with metastatic potential in testicular germ cell tumours.

Although syndecan-4 is implicated in cancer progression, there is no information for its role in testicular germ cell tumours (TGCTs). Thus, we examined the expression of syndecan-4 in patients with TGCTs and its correlation with the clinicopathological findings. Immunohistochemical staining in 71 tissue specimens and mRNA analysis revealed significant overexpression of syndecan-4 in TGCTs. In seminomas, high percentage of tumour cells exhibited membranous and/or cytoplasmic staining for syndecan-4 in all cases. Stromal staining for syndecan-4 was found in seminomas and it was associated with nodal metastasis (P = 0.04), vascular/lymphatic invasion (P = 0.01), and disease stage (P = 0.04). Reduced tumour cell associated staining for syndecan-4 was observed in nonseminomatous germ cell tumours (NSGCTs) compared to seminomas. This loss of syndecan-4 was associated with nodal metastasis (P = 0.01), vascular/lymphatic invasion (P = 0.01), and disease stage (P = 0.01). Stromal staining for syndecan-4 in NSGCTs did not correlate with any of the clinicopathological variables. The stromal expression of syndecan-4 in TGCTs was correlated with microvessel density (P = 0.03). Our results indicate that syndecan-4 is differentially expressed in seminomas and NSGCTs and might be a useful marker. Stromal staining in seminomas and reduced levels of syndecan-4 in tumour cells in NSGCTs are related to metastatic potential, whereas stromal staining in TGCTs is associated with neovascularization.

Genomic gain and over expression of CCL2 correlate with vascular invasion in stage I non-seminomatous testicular germ-cell tumours.

Testicular germ-cell tumours (TGCT) are the most frequent solid tumour to affect young Caucasian adult males and have increased in incidence over recent decades. In clinical stage I non-seminomas, (NSGCT) histological vascular invasion (VI) is a prognostic factor for metastatic relapse. Using array comparative genomic hybridization, we have previously shown that the presence of VI is associated with gain of a region at 17q12, containing a cluster of genes encoding inflammatory cytokines. We here confirm this finding using fluorescence in situ hybridization (FISH) demonstrating gain in 12 out of 42 (29%) assessable samples. Interrogation of previously published expression microarray data suggests that of the genes contained within this region, CCL2 [monocyte chemoattractant protein 1 (MCP1)] is frequently overexpressed in TGCT. Immunohistochemistry confirms this finding in a collection of 67 clinical stage I NSGCT, demonstrating an association with the presence of VI (p=0.049) that was not seen with VEGF-A, MMP2 or MMP9, although all were frequently expressed. This work gives further insight into the mechanisms involved in invasion in this tumour type, which may ultimately have implications for the management of patients with stage I disease.

4-(3-Halo/amino-4,5-dimethoxyphenyl)-5-aryloxazoles and -N-methylimidazoles that are cytotoxic against combretastatin A resistant tumor cells and vascular disrupting in a cisplatin resistant germ cell tumor model.

New combretastatin A analogues featuring oxazole or N-methylimidazole bridged Z-alkenes and halo- or amino-substituted A-rings were tested against various cancer cell lines and in testicular germ cell tumor xenografts in mice. Imidazoles with 3-halo-4,5-dimethoxy substituted A-rings and 3-amino-4-methoxy substituted B-rings (7b and 8b) were efficacious at nanomolar concentrations against cells of combretastatin A refractory HT-29 colon carcinoma, multidrug-resistant MCF-7/Topo breast carcinoma, and cisplatin-resistant 1411HP testicular germ cell tumor. They induced apoptosis and inhibited tubulin polymerization. While well tolerated by mice at high doses, these imidazoles initiated extensive intratumoral hemorrhage and regressions of highly vascularized 1411HP xenografts.

Vascularization of testicular germ cell tumours: evidence from experimental teratocarcinomas.

Testicular germ cell tumours (TGCTs) represent about 2% of male malignancies, being the most common cancer among adolescents and young adults. As in most neoplasias, TGCTs show a chaotic vascular architecture, altered blood supply and over-expression of pro-angiogenic factors, aspects closely related to tumour overgrowth and metastasis. Following this trend, our laboratory has analysed the effect of the hypoxic tumour microenvironment on cancer stem cells, particularly the expression of factors related to vascularization, such as matrix metalloproteinases, adhesion molecules, vascular endothelial growth factors (VEGF) and VEGF receptors. This review also summarizes our present knowledge on vascularization in the normal and neoplastic testis, the potential role of the factors involved in TGCT neovascularization and their importance as possible therapeutic targets.

Serum human chorionic gonadotropin is associated with angiogenesis in germ cell testicular tumors.

BACKGROUND: Germ cell testicular tumors have survival rate that diminishes with high tumor marker levels, such as human chorionic gonadotropin (hCG). hCG may regulate vascular neoformation through vascular endothelial growth factor (VEGF). Our purpose was to determine the relationship between hCG serum levels, angiogenesis, and VEGF expression in germ cell testicular tumors. METHODS: We conducted a retrospective study of 101 patients. Serum levels of hCG, alpha-fetoprotein (AFP), and lactate dehydrogenase were measured prior to surgery. Vascular density (VD) and VEGF tissue expression were determined by immunohistochemistry and underwent double-blind analysis. RESULTS: Histologically, 46% were seminomas and 54%, non-seminomas. Median follow-up was 43 +/- 27 months. Relapse was present in 7.5% and mortality in 11.5%. Factors associated with high VD included non-seminoma type (p = 0.016), AFP > or = 14.7 ng/mL (p = 0.0001), and hCG > or = 25 mIU/mL (p = 0.0001). In multivariate analysis, the only significant VD-associated factor was hCG level (p = 0.04). When hCG levels were stratified, concentrations > or = 25 mIU/mL were related with increased neovascularization (p < 0.0001). VEGF expression was not associated with VD or hCG serum levels. CONCLUSION: This is the first study that relates increased serum hCG levels with vascularization in testicular germ cell tumors. Hence, its expression might play a role in tumor angiogenesis, independent of VEGF expression, and may explain its association with poor prognosis. hCG might represent a molecular target for therapy.

Survival after an antiangiogenetic therapy and surgery in a wide spread growing teratoma originating from a testicular mixed malignant germ cell tumor.

Growing teratoma is still an often unsolved problem especially in male with mixed malignant GCTs of the testis or the mediastinum. This specific situation with progressive tumor growth and simultaneous normalization of tumor markers during or after treatment of malignant GCTs with teratomatous elements is judged as a fatal situation if this situation can not be controlled by extensive surgery, as teratoma are not sensible to chemotherapy or irradiation. Here, we report the case history of a 17-year old male patient with a testicular malignant GCT and wide spread lymph node metastases, who developed a rapidly progressive growing teratoma within the lymph node metastases. Within the molecular profile of the tumor we could find a cytogenetic picture typically found in malignant adult GCTs. In view of the bulky abdominal, thoracic and cervical metastases and the uncontrolled tumor progression, the situation was considered incurable. However, following an individual treatment attempt, this patient was treated with a four-agent combination of drugs with antiangiogenetic potential as well as low-dose cyclic chemotherapy. This approach resulted in a sustained disease stabilization followed by extensive surgical resection of the metastases. We therefore would like to highlight this treatment approach in unresectable growing teratoma and would like to stimulate further research and collaboration to come to an optimized treatment suggestion for this group of poor prognostic patients.

Sunitinib inhibits tumor growth and synergizes with cisplatin in orthotopic models of cisplatin-sensitive and cisplatin-resistant human testicular germ cell tumors.

PURPOSE: Germ cell tumors (GCT) of the testis are highly curable, but those patients who are refractory to cisplatin (CDDP)-based combination chemotherapy have a poor prognosis. Therefore, identifying new alternatives for treatment remains a priority. Several studies support an important role for angiogenesis in GCTs, suggesting that antiangiogenic treatment might be a good alternative. Sunitinib is an oral multitarget tyrosine kinase receptor inhibitor with antiangiogenic and antitumor activities. In the present study, we evaluated the effect of sunitinib, CDDP, or the combination of both drugs using an orthotopic model of human testicular GCT. EXPERIMENTAL DESIGN: Mice were implanted with four different testicular tumors: a yolk sac, two choriocarcinomas, and a CDDP-resistant choriocarcinoma variant induced in mice by continuous exposure to CDDP. Mice were treated with vehicle, CDDP, sunitinib, or the combination of both drugs and their effects on tumors were analyzed. RESULTS: We observed a significant inhibition in tumor growth accompanied by longer survival after sunitinib treatment. Combination therapy with CDDP significantly enhanced these effects. Sunitinib induced apoptosis, reduced tumor cell proliferation and tumor vasculature, and inhibited vascular endothelial growth factor receptor 1, 2, and 3 and platelet-derived growth factor receptor alpha phosphorylation without affecting phosphorylation of other tyrosine kinase receptors. More importantly, tumor growth inhibition induced by sunitinib was also observed in the induced CDDP-resistant choriocarcinoma model. CONCLUSIONS: Taken together, these results suggest that sunitinib might be a new alternative for treatment of CDDP-refractory patients.

Targeted therapies for patients with germ cell tumors.

BACKGROUND: Patients with advanced germ cell tumors can be cured with cisplatin-based chemotherapy but the outcome remains unsatisfactory for patients with relapsed disease. Targeted therapies have changed the standard of care for many advanced solid tumors. OBJECTIVE: To identify clinically available drugs that have the potential as targeted therapies in germ cell tumors. METHODS: A literature search was carried out for expression and mutation status of receptor tyrosine kinases in germ cell tumors, also a literature and clinical trial database search for completed and ongoing clinical trials with targeted therapies in germ cell tumors. RESULTS/CONCLUSIONS: c-KIT is mutated in some seminomas and bilateral germ cell tumors. Several case reports and small clinical trials with trastuzumab, thalidomide and imatinib were identified and clinical trials with sunitinib and bevacizumab are ongoing. We expect an increased use of targeted therapies in advanced germ cell tumors in the next few years.

3D perfusion mapping and virtual surgical planning in the treatment of pediatric embryonal abdominal tumors.

INTRODUCTION: 3D imaging and surgical planning for the treatment of embryonal tumors using different techniques (CT versus MRI) are presently under discussion. Up to now, the main focus has been on visualizing the anatomy. Contrast medium dynamics have not been taken into consideration. The aim of the present study was to establish the technical means of integrating the 3D images from functional MRI data into the anatomical images and to determine clinical applications for this approach. MATERIAL AND METHODS: In 11 patients (mean age: 2.4 years) with solid tumors, 26 diagnostic MRI examinations were performed for primary diagnosis, treatment monitoring, or as part of the surgical planning. Seven children presented with neuroblastomas, three with Wilms' tumor, and one with advanced bilateral nephroblastomatosis. The MRI data were acquired using a 1.5-T system. For post-processing, we used volume rendering software, including an evaluation of perfusion. By using color-coded parametric images and integrating functional information, perfusion could be visualized and used for interactive surgical planning. Macroscopic and microscopic sections served as the gold standard for assessing tissue viability. RESULTS: We were able to integrate the dynamic data into the anatomical images for all patients. A good agreement was found between the results of surgical planning, including perfusion mapping, with the surgical site, subsequently produced macroscopic sections and the results of random microscopic examinations. CONCLUSIONS: Perfusion mapping using color-coded parametric images of pediatric abdominal tumors extends the diagnostic techniques currently available. We provide first proof of the possibility of integrating functional information into 3D MR images in children. Monitoring the treatment of nephroblastoma and surgical planning for pediatric embryonal tumors represent potential applications of this technique.

Versican but not decorin accumulation is related to metastatic potential and neovascularization in testicular germ cell tumours.

AIMS: To investigate the expression of versican and decorin in patients with testicular germ cell tumours (GCTs) and to correlate this with the clinicopathological findings. Matrix proteoglycans versican and decorin are frequently overexpressed in various malignancies and are involved in the progression of cancer. METHODS AND RESULTS: Overexpression of versican and decorin was detected in GCTs by immunoblotting. Immunohistochemical staining for proteoglycans was performed on 71 cases of paraffin-embedded tissues. In most of the cases increased decorin and versican stromal staining was demonstrated. In both seminomas and non-seminomatous germ cell tumours (NSGCTs) strong staining of decorin was not found to be related to any of the clinicopathological variables. Accumulation of versican was found to be associated with vascular and lymphatic invasion, nodal metastasis and disease stage in seminomas and NSGCTs and, in addition, with tumour size and distant metastasis only in NSGCTs. Additionally, only the deposition of versican was linearly correlated with the number of microvessels in the tumour stroma in GCTs. CONCLUSIONS: Ectopic versican and decorin expression is a frequent feature in GCTs. Versican but not decorin accumulation in GCTs is related to metastatic potential and neovascularization and might be a useful marker for testicular malignancy.

Serum levels of basic fibroblast growth factor reflect disseminated disease in patients with testicular germ cell tumors.

The potential role of angiogenesis stimulators in the pathogenesis of different tumor entities has been confirmed in several studies. We measured the serum levels of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) in 51 patients with testicular germ cell tumors and in 39 healthy volunteers. Serum concentrations of bFGF, VEGF and PDGF-AB were determined by enzyme-linked immunosorbent assay. The median serum bFGF level for tumor patients was 3.46 pg/ml (range 0-61.6) compared to 0.7 pg/ml (0-11) in the control group (P<0.01). In patients with metastatic disease, the median serum bFGF level was 10.3 pg/ml (0-61.6) in contrast to 2.8 pg/ml (0-50) in patients with localized disease (P<0.01). The median serum VEGF and PDGF levels were 270 pg/ml (0-1,903) and 37,837 pg/ml (9,075-108,800), respectively, for tumor patients and 200 pg/ml (44-585) and 23,000 pg/ml (4,250-70,650) in the control group ( P<0.05). Our data suggest that angiogenesis, as reflected by serum concentrations of bFGF, VEGF and PDGF, plays a functional role in the growth and progression of testicular germ cell tumors.

Preaortic iliac venous confluence ("marsupial cava"): a rare anomaly of the inferior vena cava.

A patient was shown by computed tomography (CT) to have a rare developmental anomaly of the inferior vena cava (IVC), in which the iliac venous confluence is located anterior (rather than posterior) to the right common iliac artery. Recognition of the anomaly is important prior to surgical intervention in that area, as well as to prevent misinterpretation of the anomaly as representing adenopathy.

Tumor angiogenesis formation of vessels de novo at germ cell tumors.

Systemic studies of 346 biopsy specimens and 56 necropsy specimens with testicular germ cell tumors established two types of vessel formation: (1) classic (mature) type, representing a proliferation of the vessel system that already exists; and (2) embryonal type, with a real new formation of vessels from giant multinuclear cells. Vessels and vessel convolutes with wide lumina and thin walls are characteristic of the embryonal type. Essential properties of both types of vessel formation are presented, as well as the gradual transformation of giant multinuclear cells. The way that giant cell formations are created is described, along with their role in the tumor angiogenesis.

Prognostic indicators for failure of surveillance management of stage I non-seminomatous germ cell tumours.

Fifty-three patients presenting with non-seminomatous germ cell tumours (NSGCT) of the testis were examined. Particular interest was directed towards the association of several morphological features of the primary tumour with metastatic disease, either at presentation or later in the course of the tumour. It is apparent from this study that the presence of vascular invasion in the primary tumour, high T stage (advanced local disease) and the presence of choriocarcinoma are poor prognostic signs in NSGCT. In such tumours presenting as clinical stage I, surveillance management may not be appropriate because of the high rate of relapse.

Computerised tomography in the evaluation of expansile lesions arising from the skull vault in childhood--a report of 5 cases.

Expansile lesions of the skull vault are rare in childhood, and often present as relatively asymptomatic calvarial swellings. The cases of 5 children with expansile lesions of the skull vault due to both benign and malignant primary bone lesions are described. The value of computerised tomography in demonstrating that the "tumour" arises primarily from the skull vault as opposed to the underlying brain, and in demonstrating clinically unsuspected endocranial extension of the mass is described. The CT findings in 2 cases of aneurysmal bone cyst, including the significance of the presence of "fluid levels" in reaching a definitive diagnosis are discussed. The successful pre-operative embolisation in one case of aneurysmal bone cyst is reported.

Hysteroscopic diagnosis of malignant mixed müllerian tumor of the corpus uteri.

Hysteroscopic findings of two cases with homologous type of malignant mixed müllerian tumor of the corpus uteri are described. On hysteroscopic examination, not only were nodular or polypoid lesions with fairly smooth surfaces found but also lesions with rough uneven surfaces and dilated vessels resembling the figures of endometrial carcinoma were observed. The blood vessels of lesions with fairly smooth surfaces were not dilated. Under hysteroscopy, each lesion with a smooth surface seemed to be more closely related to a benign lesion, such as an endometrial polyp or submucous myoma. The lesions with smooth surfaces corresponded to the histologically sarcoma-dominant areas and the lesions with uneven surfaces and dilated vessels were equivalent to the sites where adenocarcinoma was noted. Thus, hysteroscopic findings of this tumor well reflected the histology near the surface of the endometrium.