Management of germ cell tumours of the ovary

Malignant ovarian germ cell tumours (OGCT) comprise only 2–5% of all ovarian cancers but are significantly different to epithelial ovarian cancers. They affect women of child bearing age and are much more curable than their epithelial counterparts. In addition, the majority of patients will retain their fertility after multimodal treatment. The small numbers of patients mean that randomised controlled trials of chemotherapy, the gold standard test of treatment effectiveness in other malignancies, have proved impossible to perform. The different types of OGCT have variable degrees of chemosensitivity and differing prognoses. Treatment outcomes are also dependent on the stage of disease at diagnosis. In this article, dysgerminomas and non-dysgerminomas are analyzed separately, as there are notable differences in their behaviour and outcomes. It is difficult to think of many diseases in which prognosis has improved as greatly as ovarian germ cell tumours and this is due to modern combination chemotherapy. Like the treatment of testicular cancer, this represents one of the successes of modern medicine.     

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.     

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.     

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.     

Chemotherapy of disseminated germ cell tumors

Current modes and issues of chemotherapy for the patients with disseminated germ cell tumors (GCTs) are described. A review of the literature of prospective randomized trials designed to compare the efficacy and toxicities between induction chemotherapy regimens for patients with either good- or poor-risk disseminated GCTs showed that three cycles of bleomycin, etoposide, and cisplatin (BEP) or four cycles of etoposide and cisplatin (EP) for good-risk GCTs, and four cycles of BEP for poor-risk GCTs, are the most effective regimens even now. A prognostic factor-based staging system can distinguish patients with either good- or poor-risk GCTs, and help make risk-based decisions about therapeutic modes. However, there is a variety of criteria that make intertrial comparison difficult. An internationally accepted prognostic classification of disseminated GCTs reported recently by the International Germ Cell Cancer Collaborative Group will resolve these problems. High-dose chemotherapy (HDCT) with autologous stem cell rescue can cure a relatively small but significant percentage of heavily pretreated patients who are deemed incurable with any other therapeutic strategy. Moreover, HDCT in first-line therapy for patients with poor-risk GCTs is now expected to improve treatment outcome obtained by BEP. Because HDCT has not totally overcome cisplatin-resistance, further investigation should be required.     

Management of malignant brain tumors

This review is made up of two parts. The first section describes techniques and methods used in the treatment of malignant brain tumors, stressing the most recent developments. The second part reviews the therapeutic modalities in malignant gliomas, where an attempt is made to consider separately glioblastomas, anaplastic astrocytomas and oligodendrogliomas, low-grade glioma, medulloblastoma, primary brain lymphoma, and brain metastases. A decision making algorithm is suggested for each tumor type.     

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.     

Sex cord-stromal and steroid cell tumors of the ovary

Gonadal cell types that derive from the coelomic epithelium (sex cords) or mesenchymal cells of the embryonic gonads include granulosa cells, theca cells, fibroblasts, Leydig cells, and Sertoli cells. Ovarian tumors of these cell types are called sex cord-stromal tumors. This group of tumors represents approximately 8% of ovarian neoplasms and affects all age groups. The more common types are granulosa cell tumors (GCTs), fibrothecomas, and Sertoli-Leydig cell tumors. Sex cord-stromal tumors are of interest partly because of their hormonal effects, which are rare for other ovarian neoplasms. These effects include estrogenic effects (pseudoprecocious puberty, endometrial bleeding, endometrial hyperplasia and carcinoma) and virilization. The variety of gross appearances of these tumors, ranging from large multicystic masses to small solid masses, would appear to preclude a specific radiologic diagnosis. However, in many patients, both clinical and radiologic clues can suggest the diagnosis, including predominantly fibrous content at ultrasound or magnetic resonance imaging (fibrothecoma), large hemorrhagic multicystic mass in a child with pseudoprecocious puberty (juvenile GCT), and associated syndromes such as Peutz-Jeghers syndrome (sex cord tumor with annular tubules) or Ollier disease and Maffucci syndrome (juvenile GCT).     

Management of malignant tumors of the salivary glands

Results of treatment for patients with salivary gland carcinoma have improved in recent years, most likely due to earlier diagnosis and the use of more effective locoregional therapy. Salivary gland tumors are treated surgically, often in conjunction with postoperative radiation therapy when the tumor is malignant. Good results rest strongly on the performance of an adequate, en bloc initial resection. Radical neck dissection in indicated in patients with obvious cervical metastasis, and limited neck dissection may be appropriate in patients with clinically negative nodes in whom occult nodal involvement is likely. Postoperative radiation therapy should be administered when the tumor is high stage or high grade, the adequacy of the resection is in question, or the tumor has ominous pathologic features. Neutron beam therapy shows promise in controlling locoregional disease but requires further study. No single chemotherapeutic agent or combination regimen has produced consistent results. At present, chemotherapy is clearly indicated only for palliation in symptomatic patients with recurrent and/or unresectable cancers. Patients with salivary gland carcinomas must be followed for long periods, as recurrence may occur a decade or more following therapy. Distant metastasis appears to occur in approximately 20% of patients.     

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.     

Differential expression of protooncogenes in human germ cell tumors of the testis

BACKGROUND: It has been suggested that tumorigenesis of the germ cell tumor of the testis includes abnormal and developmentlike differentiation of primordial germ cells to several mature type tumors. METHODS: To clarify roles of protooncogenes in the unique tumorigenic mechanism in the human germ cell tumor, the authors examined the expression of 15 protooncogenes in human primary germ cell tumors of the testis with Northern blot analyses. RESULTS: Fifteen (94%) of 16 seminomas and 5 (83%) of 6 embryonal carcinomas had a significant levels of N-myc expression, whereas they did not express two receptor type protooncogenes, c-erbB-1 and c-erbB-2. In contrast, some immature teratomas had a high level of c-erbB-1 expression, and an advanced case showed a significant level of c-erbB-2 expression. Immature teratomas did not show N-myc expression. Higher levels of c-mos expression were observed in several cases of seminomas and embryonal carcinomas. Expression of c-Ki-ras or N-ras was observed in all histologic subgroups and normal testes. CONCLUSION: A significant level of N-myc expression may be essential for undifferentiated tumors including seminoma and embryonal carcinoma, whereas c-erbB-1 and possibly c-erbB-2 may have important roles in the differentiated tumors such as immature teratoma. These results suggest that some of the protooncogene expression may be switched critically during the differentiation from seminomas or embryonal carcinomas to the more differentiated-type tumor.     

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.