Pediatric germ cell tumors

Germ cell tumors are relatively rare tumors in childhood which often present with very large tumors in both gonadal and extragonadal locations. Extragonadal tumors are more common in neonates and infants, whereas gonadal sites predominate in childhood and adolescence. Management consists of surgical resection for localized disease, chemotherapy for residual or metastatic disease, and neoadjuvant chemotherapy and delayed surgical excision for unresectable lesions. The survival for children with germ cell tumors has improved significantly over the past 2 decades with the development of platinum-based chemotherapy. Mature and immature teratomas at any site, and completely resected (Stage I) malignant gonadal and extragonadal tumors, are treated with surgical excision and observation. Malignant lesions with microscopic residual, lymph node disease, or metastatic disease receive platinum-based chemotherapy. Current survival for low-stage (Stages I and II) gonadal sites approaches 100% and survival for higher stage (Stages III and IV) gonadal sites is approximately 95%. Survival for extragonadal lesions is approximately 90% for Stages I and II and 75% for Stages III and IV.     

Therapy for good risk germ cell tumors

BACKGROUND: Duodenal mucosal biopsies are routinely taken for diagnosis in children with complaints of the upper gastrointestinal tract. Surprisingly, little is known about the usefulness of proximal duodenal versus distal duodenal biopsies for routine diagnostic purposes. This study evaluated the comparability of proximal and distal duodenal biopsies with respect to mucosal morphology as well as glycohydrolase expression as an indicator of intestinal epithelial function. METHODS: Specimens obtained in duodenal endoscopic biopsies from 64 children, ranging in age from 3 months to 18 years with normal or affected mucosa, were studied. Biopsies were performed in anatomically defined regions in the bulbus duodeni (the very proximal part of the duodenum) and distally of the papilla of Vater (distal of the pancreatic duct). Biopsy specimens were paraformaldehyde-fixed for histologic examination and immunohistochemical evaluation or were homogenized to isolate RNA. Crypt/villus morphology was assessed as is routinely determined by pathologists. In addition, several aspects of lactase and sucrase-isomaltase expression as paradigms of intestinal brush border enzymes were assessed: localization at the cellular level, semiquantitative immunohistochemistry, and quantitative measurement of the messenger RNA levels of the respective brush border glycohydrolases. RESULTS: As anticipated, there was a wide interpatient variation in mucosal morphology and expression of lactase and sucrase-isomaltase. Nonetheless, the consistent finding was that in each patient, measurements of morphology and lactase and sucrase-isomaltase gene expression were very similar between samples obtained in the proximal and distal biopsies. CONCLUSIONS: Biopsies performed in either location in the duodenum are equally suitable for diagnostic workup of patients suspected of mucosal abnormalities affecting morphology or small intestinal brush border glycohydrolase activities.     

Ovarian germ cell tumors: an update

Study of an amorphous phase in plasma-sprayed hydroxyapatite (HA) coatings is important owing to its unique characteristics and nonnegligible amount of the amorphous phase compared to crystalline HA. However, little is known about the component parts of an amorphous phase. It is known that amorphous phase usually appears as the diffusion maximum (Dmax) in X-ray diffraction (XRD) patterns. Analyzing Dmax, including the position (Pmax) and area of Dmax, we can indicate the component parts of an amorphous phase and their transitions. In this study, the variation of Dmax in XRD patterns of the coatings during plasma spraying, in postheating, and in dissolving in vitro was studied with the aid of XRD. It was found that component parts of the amorphous phase in the coating varied with increasing thickness, consisting of two part represented by Dmax1, located between 29.4 and 29.8 degrees (2 theta), and Dmax2, located between 31.0 and 31.4 degrees (2 theta). It was concluded that Dmax3, located between 32.0 and 32.4 degrees (2 theta), should be referred to as nanocrystals of HA. In addition, the particle size of the starting powder may affect the component parts of the amorphous phase in the coating in addition to thickness. With vacuum heating (650 degrees C) and water vapor treatment at a low temperature (125 degrees C) in a saturated vaporic atmosphere, transition of the amorphous components was not as efficient as that at 490 degrees C with water vapor. The reason might be that the amorphous-to-crystalline HA conversion is dependent on both temperature and water vapor pressure. It was found that amorphous components were transformed completely into crystalline HA after heating at 490 degrees C with a partial water vapor pressure of 0.01 MPa for 2 h. It was concluded that the unstable amorphous components (Dmax1, Dmax2) converted into more stable nanocrystals of HA (Dmax3). Degradation in vitro showed that Dmax3 was more stable than Dmax1 and Dmax2. It was concluded that nucleation of apatite in vitro should be attributed to nanocrystals of HA (Dmax3) except for the amorphous components. It is recommended that the optimal phasic contents of the plasma-sprayed HA coating be mainly composed of crystalline HA and nanocrystals of HA (Dmax3) in terms of the stability and biocompatibility of the coating.     

Management of malignant germ cell tumors of the ovary

A high sensitive method for detecting the change of microsomal membrane surface oligosaccharides was developed to study the regulatory role of lipid- or peptide-linked mannoside of endoplasmic reticulum in synaptic functions. The binding of concanavalin A to the microsomal membrane surface was measured quantitatively using a microgram-order of rat brain microsomal proteins. The fluorescence polarization of concanavalin A (Con A)-fluorescein isothiocyanate (FITC) conjugate bound to the membrane was analyzed to quantitate the change of binding constant and the number of binding sites. As a control, the non-specific binding of bovine serum albumin-FITC conjugate was measured by the same technique. We measured the change of fluorescence intensity of membrane-bound FITC conjugates by the flow cytometry and found that the intensity of FITC conjugate bound to the membrane increased more than that of free form of the probe. We observed that the alpha-mannosidase-treatment of rat brain microsomes resulted in the increase of binding constant of Con A to the microsomal surface without significant loss of binding sites.     

Secondary neoplasms following treatment of malignant germ cell tumors

PURPOSE: The current study investigates the frequency and outcome of secondary malignancies in patients treated for testicular cancer at Hannover University Medical School between 1970 and 1990. PATIENTS AND METHODS: One thousand twenty-five patients with a median follow-up duration of 61 months (range, 12 to 240) were included in the analysis. Follow-up was complete in 1,018 patients (99%). Histology was seminoma in 324 patients (38.7%) and nonseminomatous germ cell tumor in 624 patients (61.3%). At the time of median follow-up, 814 patients (79.9%) were alive. RESULTS: Fourteen patients developed a secondary neoplasm (cumulative incidence, 1.38%; 95% confidence interval [CI], 0.75 to 2.30); 13 patients had solid tumors and one had secondary lymphoblastic leukemia with a t(4; 11) translocation including band 11q23. None of 224 patients on surveillance strategy (with or without retroperitoneal lymph node dissection [RPLND]) developed a second neoplasm, compared with four of 413 patients (0.97%; 95% CI, 0 to 1.9) after cisplatin-based chemotherapy (not significant) and nine of 332 patients (2.7%; 95% CI, 0.9 to 4.5) after radiotherapy (P = .02). The cumulative incidence of a secondary neoplasia of 1.76% (95% CI, 0.97 to 2.94) in patients treated by radiotherapy and/or chemotherapy was significantly higher compared with patients on surveillance protocols (P = .03). Chemotherapy containing standard-dose etoposide did not increase the risk of occurrence of secondary neoplasms. A significantly elevated relative risk of 7.53 (range, 3.4 to 14.3) compared with the male German population was only found for patients treated by radiotherapy. CONCLUSION: Compared with patients who have other curable malignant tumors, an incidence of 1.38 of secondary neoplasms after a median follow-up duration of 61 months is low. The highest risk for secondary neoplasia after treatment of testicular cancer is associated with the use of radiotherapy. Following chemotherapy, no significantly elevated risk was observed. In conclusion, the benefits of curative treatment far outweigh the risk of secondary cancer in patients with malignant germ cell tumors.     

Sexual functioning after multimodality treatment for disseminated nonseminomatous testicular germ cell tumor

PURPOSE: We determined sexual functioning after chemotherapy for disseminated nonseminomatous testicular germ cell tumor, and evaluated the impact of resection of post-chemotherapy residual retroperitoneal tumor. MATERIALS AND METHODS: A total of 155 consecutive patients treated with chemotherapy for disseminated nonseminomatous testicular germ cell tumor (between 1980 and 1994) was questioned about their sexual functioning. The patients were divided in 2 subgroups: patients treated with or without resection of post-chemotherapy residual retroperitoneal tumor. Volume and location (divided into left para-aortal or right paracaval/interaortacaval) of the resected tumor were related to absence of ejaculation as well as decreased semen amount. In addition, libido, arousal, erection and orgasm were related to ejaculatory dysfunction. RESULTS: A total of 43 patients (27.7%) was treated with chemotherapy only and 112 (72.3%) had additional resection of post-chemotherapy residual retroperitoneal tumor mass. Overall, 22.4% reported loss of libido, 14.1% decreased arousal, 16% erectile dysfunction, 23.1% decreased orgasmic intensity, 17.4% decreased semen amount and 18.7% complete absence of antegrade ejaculation. With exception of absence of ejaculation, sexual dysfunctions were reported in similar frequencies in both treatment subgroups. In the resection of post-chemotherapy residual retroperitoneal tumor subgroup, 25.9% of the patients had complete absence of ejaculation. The other sexual dysfunctions were related neither to decreased semen amount nor to complete absence of ejaculation. The mean volume of resected tumor was higher (95 cm.3) in patients with absence of ejaculation than in those without (40 cm.3), and patients with right paracaval/interaortacaval tumor (20 of 58, 34.5%) reported more often absence of ejaculation than those with left para-aortal tumor (9 of 54, 16.7%). CONCLUSIONS: In patients treated for disseminated nonseminomatous testicular germ cell tumor, post-chemotherapy sexual morbidity cannot be neglected. Except for loss of antegrade ejaculation, sexual dysfunctions are not related to resection of post-chemotherapy residual retroperitoneal mass. A high volume of tumor and a right paracaval/interaortacaval location predispose to loss of antegrade ejaculation.     

Cytogenetics of the progression of adult testicular germ cell tumors

The multifunctionality of adhesion receptor ligands as well as the promiscuous nature of vascular integrins and nonintegrin-dependent adhesive interactions allow ligand-receptor binding of variable strength. The cooperation with pericellular proteolysis cascades is required for vascular remodelling during angiogenesis, atherogenesis or inflammatory processes. In particular, integrin-dependent cell contact, spreading and (trans-)migration can be modulated by ECM-associated PAI-1 and uPA-receptor driven reactions that are intimately linked to the invasive potential of cells. Recently, mechanisms of molecular crosstalk between these receptor systems have been recognized: (a) uPA-receptor may directly interact with beta 1- and beta 2-integrins on circulating blood cells; (b) av beta 3-integrin-directly binds to a matrix metalloproteinase; (c) uPA and PAI-1 balance the high affinity binding of vitronectin to uPA-receptor; (d) vitronectin-dependent cell adhesion and migration involving alpha v-integrins or uPA-receptor are blocked by active PAI-1 independent of its role as protease inhibitor. These results are compatible with vascular injury studies in uPA- and PAI-1 knock-out mice and provide new targets for the treatment of diseases associated with imbalanced vascular remodelling.     

Synchronous bilateral testis tumor: mixed germ cell and theca cell tumors

Synchronous bilateral testis tumors of different histologic types are rare. All previous cases have demonstrated germ cell tumors on both sides. The simultaneous appearance of a germ cell tumor and a contralateral non-germ cell tumor has not been reported. We herein report a thirty-four-year-old man who presented with a mixed non-seminomatous germ cell tumor of the left testis and theca cell tumor of the right testis.     

High-dose chemotherapy with autologous stem cell support in poor-risk germ cell tumors

We propose a simple and fast method of detecting apoptosis using an automated hematology analyzer. Detection is based on cellular optical light scatter properties and demonstration of the membrane fragility which characterizes cells undergoing the process of apoptosis. As part of it's routine leucocyte differential analysis, the Abbott Cell-Dyn 4000 collects multi-angle cellular light scatter data. In addition red fluorescence (FL3) emitted by cells following propidium iodide labeling is collected. This provides quantitation of both the erythroblast count and a leukocyte viability index (WVF). Fresh or cryopreserved peripheral blood cells from 17 B-chronic lymphocytic leukemia (B-CLL) patients were incubated in presence of theophylline, fludarabine or in medium alone. After 36-hrs of culture the percentage of apoptotic cells of the sample was determined from the parameters of the CD 4000 described above and thereafter this was compared with reference methods for estimation of apoptosis. The reference methods used were in situ detection of cell death on slides (TUNEL test) and also flow cytometry (Annexin V). Results showed an excellent correlation between the 3 techniques. This rapid, easy and reliable method of quantifying apoptosis may be very useful means of routinely predicting the response to chemotherapy.     

Mature teratoma identified after postchemotherapy surgery in patients with disseminated nonseminomatous testicular germ cell tumors: a plea for an aggressive surgical approach

BACKGROUND: Mature teratoma is often found in resected retroperitoneal residual tumor masses (RRTM) after chemotherapy for disseminated nonseminomatous testicular germ cell tumors (NSTGCT). The aim of this report is to describe the clinical course of patients after resection of residual teratoma, with particular emphasis on relapse with either growing mature teratoma or secondary non-germ cell malignancy. METHODS: During the period 1979-1995, 113 patients underwent a laparotomy for resection of RRTM after chemotherapy for NSTGCT. Only patients with mature teratoma in the RRTM were included in the current study, and data on the patients who experienced relapse were studied in detail. RESULTS: Mature teratoma was found in 51 patients (45.1%) with RRTM resected after chemotherapy. Nine of these 51 patients (17.6%) relapsed; the relapses resulted from growing mature teratoma in 5 patients (9.8%), secondary non-germ cell malignancy in 3 patients (5.9%), and recurrent germ cell malignancy in 1 patient (2.0%). The primary treatment for all relapsing patients was surgical excision. All five patients with growing mature teratoma are alive without evidence of disease, as is the patient with recurrent germ cell malignancy. One of the three patients with non-germ cell malignancy died of disease, and the remaining two are alive with disease. CONCLUSIONS: Long term follow-up after resection of postchemotherapy residual teratoma is indicated because a proportion of patients develop growing mature teratoma or a secondary non-germ cell malignancy. The treatment for these recurrences should be complete surgical excision.     

Genetic analysis of ovarian germ cell tumors by comparative genomic hybridization

Ovarian germ cell tumors (OGCTs) show a heterogeneity that is not seen in their testicular counterparts and include benign mature cystic teratomas, intermediate immature teratomas, malignant germ cell tumors [GCTs (dysgerminomas, endodermal sinus tumors, and mixed GCTs)], and GCTs arising in dysgenetic gonads of 46,XY individuals. Comparative genomic hybridization was used to analyze 27 OGCTs for regions of relative gain or loss. The analysis of 21 malignant OGCTs (12 dysgerminomas, 6 endodermal sinus tumors, and 3 mixed GCTs) demonstrated genetic alterations similar to those reported in adult testicular GCTs. The most common regions gained include chromosomes 12p (16 of 21 tumors), 21 (10 of 21 tumors), 8 (8 of 21 tumors), and 1q (6 of 21 tumors). The most common region lost was chromosome 13. Regions of high-level gain were identified at 12p11-12 and 4q11. The profile of gains and losses was similar in the different histological subtypes within this category. One tumor presented in a 46,XY patient; this tumor was diploid and showed a gain of 12p. Immature teratomas (six cases) showed only one case with an abnormality, which was a gain of chromosome 14. We conclude that malignant OGCTs are genetically similar to those found in the adult testis; however, immature teratomas show no consistent gains or losses and are therefore different from those presenting in the adult testis. A review of the literature suggests that genetic abnormalities in this group may herald a worse prognosis. Lastly, OGCTs in dysgenetic gonads arise in a diploid rather than a tetraploid cell line, yet they also show a gain of 12p.     

Medical and surgical management of pulmonary metastases from germ cell tumors

Campylobacter jejuni strains are able to produce at least two different cytotoxins called "cytolethal distending toxin" (CLDT) and "cytolethal rounding toxin" (CLRT). In this study, we investigated the corresponding changes in CHO-K1 cells using the cell counter and analyzer system CASY 1. Determination of the cell volume after toxin treatment of the cells is a useful criterion for differentiation between the cytotoxic activities produced by Campylobacter strains. Incubation of the cells with crude CLDT resulted in a decrease in the cell count combined with a dramatic increase of the mean cell volume in comparison to the control culture. A decrease in the cell count was also seen as a response to CLRT preparations, while this toxin had no effect on the mean cell volume determined. It was shown that only CLDT caused histone-associated DNA fragments in the cytoplasm of CHO-K1 cells indicating an apoptotic pathway of cell death. In addition, the polymerase chain reaction (PCR) was employed to screen Campylobacter strains for the presence of the cdtB gene sequence, which was detectable in all strains investigated.     

A phase II trial of paclitaxel in refractory germ cell tumors

BACKGROUND: A significant percentage of patients with refractory germ cell tumors will not respond to standard salvage regimens. Thus there is a need for new active agents. Paclitaxel has demonstrated activity against a variety of solid tumors in both laboratory and clinical studies. METHODS: Eighteen patients with refractory germ cell tumors who failed initial cisplatin-based chemotherapy and a maximum of 2 salvage regimens were enrolled into a Phase II trial of paclitaxel at a dose of 170 mg/m2 by intravenous infusion over 24 hours every 21 days without growth factor support. The median age of the patients was 32.5 years (range, 18-49 years). The testis was the primary site of tumor for 13 patients (72%) and the tumor was extragonadal in 5 patients (28%). Six patients (33%) were late recurrences. Twelve patients (67%) had > or = 2 metastatic sites. The median number of previous chemotherapy cycles was six (range, four to nine). Three patients (17%) previously had undergone autologous bone marrow transplantation. RESULTS: Two patients (11%) responded to paclitaxel. Major toxicities were Grade 3-4 neutropenia (55% of patients) and Grade 3-4 neurotoxicity (2 patients). Neutropenic fever occurred in 3 patients (17%). CONCLUSIONS: Paclitaxel demonstrated minimal activity in heavily pretreated patients with multiple, poor risk clinical features. These results in part may be due to the unfavorable characteristics of the patients in the current study, specifically the high percentage of patients with late recurrences and extragonadal primary tumors, both of which are known to respond poorly to salvage therapy. Other trials with different patient populations and doses of paclitaxel reported response rates ranging from 13.3%-26%. The role of paclitaxel in the treatment of patients with refractory germ cell tumors remains to be defined in future studies.     

Medical treatment of ovarian malignant germ cell tumors in the adult

Malignant ovarian germ cell tumors are infrequent neoplasms that usually affect young and otherwise healthy females. The outcome of patients has been significantly improved by the introduction of cisplatin-based chemotherapy. After conservative surgery which both establishes the diagnostic and initiates therapy, the postoperative management should be adapted to histological type as well as to tumor stage. In patients with nonseminomatous germ cell tumors, the standard treatment is a combination of bleomycin, etoposide and cisplatin (BEP protocol). The number of cycles to be given is 3 when surgery is optimal, and 4 in patients with residual or metastatic disease. In patients with pure dysgerminomas, 4 cycles of BEP are the optimal treatment for advanced stages. In early stages, the alternative to chemotherapy (3 cycles of BEP) is radiotherapy, typically given to the ipsilateral hemipelvis and para-aortic nodes. Results are satisfactory with a long-term survival rate ranging from 80 to 100%, and a minimal toxicity yielding a reasonable probability of having normal offspring.