Telomerase activity in germ cell cancers and mature teratomas.

BACKGROUND: An inverse relationship has been reported between the presence of telomerase enzymatic activity and the induction of differentiation in human tumor cell lines. Male germ cell tumors represent an attractive clinical model to assess this relationship further because high telomerase activity is present in normal germ cell progenitors and in embryonal carcinomas that can differentiate into mature teratomas. To investigate how telomerase activity and the differentiation state of germ cell tumors are related, telomerase activities and telomere lengths were measured in benign testicular tissues, germ cell cancers, and mature or immature teratomas. METHODS: By use of a modified telomeric repeat amplification protocol (TRAP) assay, telomerase activity was measured in four specimens of benign testicular tissue, in 27 germ cell cancers, in seven mature teratomas, and in one immature teratoma. Telomere lengths were measured in all specimens by restriction digestion of genomic DNA and Southern blot hybridization analysis. Associations between telomerase activity and tissue histopathology were assessed with two-sided Fisher's exact tests. RESULTS: Telomerase activity was detected in all examined germ cell cancers and in the benign testicular tissue specimens. In marked contrast, telomerase activity was not detected in any mature teratoma (P<.0001). Very long telomeres were detected in some mature teratomas, consistent with telomerase repression as a late event in teratoma formation. The immature teratoma, with malignant transformation, had high telomerase activity. CONCLUSION: Telomerase is active in germ cell cancers and repressed in mature teratomas. The absence of telomerase activity may contribute to the limited proliferative capacity of mature teratomas. These findings support the existence of an inverse relationship between telomerase activity and the differentiation state of clinical germ cell tumors.     

Results of the treatment of intracranial germ cell tumors

Presented is a retrospective study of 20 patients with intracranial germ cell tumors who the authors have treated during past 10 years. The cases among these patients included thirteen germinomas, three teratomas, two embryonal carcinomas, and two malignant teratomas. A ventriculoperitoneal shunt was installed in 15 cass and the tumor was surgically removed in four cases. All cases were irradiated with 33 to 61 Gy; in 18 cases, more than half of the total dose was delivered to the whole brain, and in 9 cases, spinal irradiation was given because of a verified CSF dissemination. Chemotherapy was the regimen for four cases. The tumor responded to therapy in 16 (84%) of 19 evaluable cases. Overall, the median and five year survival were 102 months and 83%, respectively. The survival rate was found to vary between the benign group (germinoma, teratoma) and the malignant group (embryonal carcinoma, malignant teratoma, germinoma with STGC) (p less than 0.01).     

Pathobioogy of intracranial germ-cell tumors: Immunochemical,immunohistochemical, and electron microscopic investigations

Summary In an attempt to clarify the pathobiology of intracranial germ-cell tumors, we studied 56 patients with these tumors, both clinically and pathologically. Our evaluations included immunochemical, immunohistochemical, and electron microscopic observations. Thirty tumors originated in the pineal region, ten in the suprasellar region, nine in the basal ganglia, and two in other regions. Five had double sites of origin. Histologically, there were 39 germinomas, six teratomas, four embryonal carcinomas, two choriocarcinomas and five mixed tumors. Among tumors tested immunochemically, serum carcinoembryonic antigen (CEA) was positive in 3.4%, serum alpha-fetoprotein (AFP) in 25.8%, and serum human chorionic gonadotropin (HCG) in 32.1%. In CSF, CEA was positive in 14.3%, AFP in 26.3%, and HCG in 75%. One third of germinomas were positive for serum HCG, and 88.9% for CSF HCG. One half of teratomas were positive for CEA of CSF. In immunohistochemical testing, the positive rates for CEA, AFP, HCG, and placental alkaline phosphatase (PLAP) were 26.9%, 11.5%, 24.1%, and 55.6%, respectively. Most teratomas were positive for CEA and the reactions were prominant in gland-like structures. HCG-positive syncytial cells were found in three germinomas and two embryonal carcinomas as well as in choriocarcinomas. The majority of germinomas were positive for PLAP and the reactive sites were tumor cell membranes and cytoplasm. On electron microscopy, germinomas were least differentiated, followed in order by embryonal carcinomas, choriocarcinomas, and teratomas. Further clinical and pathological studies will be necessary for a better understanding of the biology of these tumors.     

Primary intracranial germ-cell tumors. A retrospective analysis with special reference to long-term results of treatment and the behavior of rare types of tumors

Thirty cases of primary intracranial germ-cell tumors were reviewed with reference to the effect of treatment. Histologically, there were 23 pure germinomas, while the remaining tumors had more unusual histology; 3 of these were teratomas, and 4 germ-cell tumors with the admixture of yolk sac tumor (YST) or embryonal carcinoma (EMC). Three of these rare cases are presented. The performed surgery and radiotherapy, seemed adequate for pure germinomas, and all these cases lived tumor-free after an observation time of 13 to 139 months although 4 patients developed intellectual retardation or cerebral dullness after radiotherapy. Four cases with YST and EMC elements, indicated by the elevation of AFP and HCG values in serum, were resistant to radio- and chemotherapy and developed, despite surgically total removal of the tumor, intra- or extracranial metastases. A review of the literature is included.     

Primary spinal yolk sac tumor with brain metastasis: case report and review of the literature

SummaryObject Central nervous system primary germ cell tumors are typically pineal or suprasellar. Primary germ cell tumors of the spinal axis are very rare, with only a few case reports of germinomas and teratomas described in the literature.Methods We present the unique case of a 25-year-old woman with an intradural, extramedullary primary yolk sac tumor (YST) at and below the level of the conus medullaris. The patient was treated with a subtotal resection and within a month had rapid regrowth of her YST. She was subsequently treated with four cycles of chemotherapy (intravenous cisplatin and etoposide), 40-Gy fractionated focal external beam radiation to the spine, and consolidation with four additional cycles of chemotherapy (intravenous carboplatin, vinblastine, etoposide, and bleomycin). Despite an initial reduction in tumor size and clinical improvement in her neurologic exam, she re-presented a year after surgery with gross enlargement of her spinal tumor and CSF dissemination with metastasis to her brain. Despite further chemotherapy and radiotherapy, the patient died from her disseminated YST.Conclusions This case demonstrates that primary YSTs may occur in the spine, and like their intracranial counterparts, are associated with poor prognosis and dissemination through the neuroaxis. When feasible (no evidence of CSF dissemination, metastasis, or multifocal disease), optimal treatment includes as extensive resection of tumor as possible followed by adjuvant chemotherapy and radiation. The authors review the available literature on the treatment of intracranial malignant germ cell tumors, extrapolated to apply to the much rarer spinal lesions.     

Modified grading system for clinical outcome of intracranial non-germinomatous malignant germ cell tumors

This study investigated the clinical outcome of intracranial non-germinomatous malignant germ cell tumors (NGMGCTs). All histologically proven cases of NGMGCTs treated in Shanghai Huashan Hospital, Fudan University were reviewed. A total of 39 cases were analyzed. There were 15 mixed germ cell tumors, 15 immature teratomas, 7 embryonal carcinomas and 2 yolk sac tumors. Patients were treated surgically first, followed by radiotherapy and/or chemotherapy. Some patients also received gamma knife surgery. The common 5-year survival rate was 36.8%. According to Matsutani's grading system, the 5-year actuarial survival rate for patients in the intermediate and poor prognosis groups were 45.8 and 14.3%, respectively. Individual analysis of each type of tumor showed that the median survival time of embryonal carcinoma was 27 months, which is very close to that of the intermediate group (28 months). We therefore classified embryonal carcinoma into the intermediate group where the 5-year actuarial survival rate for patients in the new intermediate prognosis group was 42.6%. Further analysis of immature teratoma cases found that the 5-year survival rate of patients with immature teratoma who received gamma knife surgery is 100%. This rate exhibited a significant difference (P=0.0049) compared to that of patients who did not undergo gamma knife surgery. In conclusion, we consider surgery as the first choice of treatment although for different histologis, the type of the tumor should be treated separately.     

Glutathione sulfhydryl transferase-pi expression in testicular germ-cell tumors - an immunohistochemical study of 30 cases

Glutathione sulfhydryl transferase (GST) is believed to play a major role in the detoxification of chemotherapeutic agents and therefore is thought to be important in chemoresistance. Thirty primary testicular germ cell tumors were stained immunohistochemically for GST pi using a rabbit polyclonal antibody and formalin-fixed paraffin-embedded tissue. There were 12 pure seminomas and 18 mixed germ cell tumors (GCTs). Immunostaining of each element present was graded as negative (-), weakly positive (+), or strongly positive (++). The results were as follows: seminoma (8/17 +, 9/17 ++); embryonal carcinoma (1/13 -, 7/13 +, 5/13 ++); mature teratoma (9/9 ++); immature teratoma (7/7 +); endodermal sinus tumor (7/8 +, 1/8 ++); and choriocarcinoma (1/1 -). These results show that variability exists in the expression of GST pi between different tumor types and between different examples of the same tumor type. Strongest expression was seen in seminomas and mature teratomas while other germ cell elements tended to show weaker staining. The staining patterns showed no apparent correlation with stage or response to therapy.     

Primary central nervous system germ cell tumors

Opinion statement The prognosis of primary germ cell tumors (germinal neoplasms) of the central nervous system varies, depending on the histology and size of tumor and the extent of disease at diagnosis. Although some patients receive therapy without a tissue diagnosis, it is strongly recommended that tumor tissue samples be obtained for accurate histologic diagnosis. Modern neurosurgical navigation techniques have made tissue sampling by stereotactic biopsy a safe and rapid method of determining tumor histology. Depending on tumor location, open surgical biopsy may be required in some patients. Typically, germinomas are exquisitely radiosensitive, although pre-irradiation chemotherapy reduces the total radiation exposure and may increase the cure rate. Induction cisplatin-based chemotherapy, followed by low-dose involved field radio-therapy, has excellent overall and relapse-free survival rates and is the optimal treatment for patients with germinomas. This combined chemoradiotherapy approach is associated with minimal endocrinopathy and minimal neurocognitive dysfunction. Patients with relapses after low-dose radiation therapy can respond well to salvage therapy (chemotherapy or chemoradiotherapy) without significant sequelae. Patients with nongerminomas respond best to chemotherapy combined with radiation, although the response and cure rates are lower compared to germinomas. Patients with residual masses and normal tumor markers after primary therapy should have a second-look resection because most patients have residual teratoma or necrotic tissue and can be spared additional chemotherapy or radiation. Pure mature teratomas are cured only by surgical extirpation. Immature central nervous system teratomas appear to benefit from radical surgical resection, but higher doses of locally directed radiotherapy are required with no benefit from the usual chemotherapy.     

Value of five tumor markers (AFP, CEA, hCG, hPL and SP1) in diagnosis and staging of testicular germ cell tumors

Serum levels of AFP, CEA, hCG, hPL and SP1 were measured by specific radioimmunoassays in 111 patients with testicular germ cell tumors. Seminomas, mature teratomas and "pure type" embryonal carcinomas, as well as the latter two types of tumor with seminomatous admixture, do not produce markers unless in advanced stages when they may do so (small amounts of hCP, hPL and SP1). Tumors composed of yolk-sac elements alone or mixed with embryonal carcinoma produce AFP: of syncytiotrophoblastic elements - hCG, hPL or SP1; and teratomas with differentiated structures - CEA. Compound tumors can produce any of the five markers. When present in serum after orchiectomy or lymphadenectomy, the markers are useful both in diagnosis of the tumor elements that metastasized and in staging; whereas their absence does not exclude regional or distant metastases which may contain only marker-negative elements, e.g., due to changes in tumor histology. Measurement of the serum levels of the markers informs about the remaining regional tumor elements or latent metastases and therefore is more useful than immunoperoxidase staining which provides information on the already dissected structures only.     

Retroperitoneal germ cell tumors in childhood. A clinical and pathologic study of 11 cases

During the last 54 years at the Children's Hospital 11 children (10 female, 1 male) had been treated for an extragonadal germ cell tumor arising in the retroperitoneum. There were eight teratomas (five mature, three immature), two endodermal sinus tumors and one tumor with a mixture of both components. Abdominal pain or discomfort was the usual presenting complaint, with the average age at diagnosis being 18 months. On physical examination, each child had a palpable abdominal mass usually localized in the upper quadrants. The finding of calcification, bone or teeth, on radiologic study was most helpful in establishing a preoperative diagnosis of teratoma. The preferred treatment for children with mature and immature teratomas is complete surgical resection; decisions regarding adjuvant therapy for patients with immature tumors must be evaluated on an individual basis. The prognosis remains guarded for children with unresectable primaries or those with endodermal sinus tumor. Of three tumor-related deaths, two were due to metastatic endodermal sinus tumor and one resulted from extensive local growth by immature teratoma. Successful management of children with endodermal sinus tumor requires surgery aimed at debulking or complete resection in combination with aggressive adjuvant chemotherapy.     

The treatment of cranial germ cell tumours

Germ cell tumours of the central nervous system (CNS) include many subtypes whose response to treatment varies, even though the symptoms and radiological appearances are similar. Five-year survival rates are 96% for germinomas, 100% for mature teratomas, 67% for immature teratomas and 69% for immature teratomas mixed with germinomas; for beta-HCG secreting germinomas the rate is only 38%. Patients with choriocarcinoma, embryonal carcinoma, or yolk sac tumour have the lowest survival rates; patients with germinoma or mature teratoma have longer survival rates.Although a wider resection is associated with a higher rate of survival for patients with non-germinomatous germ cell (NGGC) tumours, to date an aggressive surgical approach has been advocated only for pineal region tumours, but not for hypothalamic/neurohypophyseal tumours. Beside the delayed injury induced by radiotherapy, the late injury induced by chemotherapy is becoming increasingly evident. Cisplatin is considered an indispensable drug, but it may cause renal damage, ototoxicity, peripheral neuropathy and sterility, while etoposide is associated with an excess frequency of second neoplasms.Taking into account all of the published literature, the following therapeutic options are suggested: in pure germinoma tumours (GT) radiotherapy alone will usually ensure adequate control of the disease, and the long-term sequelae may be limited by reducing the dose delivered, as was proposed for germ cell testicular tumours, to 30 Gy to limited fields plus 25-30 Gy to the spinal axis if there is disseminated disease. In cases of recurrence, which should be uncommon, patients may be rescued with both radiotherapy and chemotherapy.In NGGC tumours, the prognosis is more unfavourable and there is often dissemination to the spine at diagnosis; however, the tumour's high chemosensitivity suggests neoadjuvant treatment chemotherapy with cisplatin and etoposide for three cycles followed by consolidation radiotherapy with 40 Gy to the limited fields plus 30 Gy to the spinal axis if disseminated.In our opinion, a higher dose of radiotherapy in cases in which chemotherapy does not achieve a radiological complete remission is not advisable, because very often the residual radiological abnormality does not represent biologically active tumour but differentiated forms such as mature teratoma.The challenge for 2000 is to both cure these patients, and avoid the late and permanent sequelae of radiation and/or chemotherapy that may subsequently impair quality of life.     

C-kit Expression in Germinoma: An Munohistochemistry-based Study

Summary In our immunohistochemical study of 25 human primary intracranial germinomas and germinomas with syncytiotrophoblastic giant cells (STGC), we stained the same sections for c-kit and placental alkaline phosphatase (PLAP). Immunohistochemical expression was graded using a semi-quantitative scoring system where 3+ = 51–75%, and 4+ = 76–100%. Of the 25 cases, 7 (28%) were graded 3+ and 18 (72%) 4+ for c-kit; 8 (32%) were 3+ or 4+ for PLAP. All 3 cases negative for PLAP-staining were strongly positive and all embryonal carcinomas, immature teratomas, and yolk sac tumors were negative for c-kit staining. The soluble isoform of c-kit (s-kit) is reportedly detectable in cerebral spinal fluid of patients with germinomas and germinomas with STGC. C-kit and s-kit may be powerful tumor markers for germinomas with or without STGC.     

Histogenetic analysis of ovarian germ cell tumors by DNA fingerprinting.

The histogenesis of ovarian germ cell tumors (11 mature teratomas, three malignant transformations of mature teratomas, two immature teratomas, and four dysgerminomas) was investigated genetically using minisatellite DNA probes 33.15 and 33.6 for person-specific restriction fragment length polymorphism (DNA fingerprint) analysis. The DNA fingerprints of six ovarian teratomas were identical with those of mononuclear cells from each host, while some polymorphic bands observed in the host mononuclear cells were lost in the DNA fingerprints of the other five cases. The cases of malignant transformation of mature teratoma and immature teratoma showed that some polymorphic bands of DNA fingerprints from the host mononuclear cells were absent in the tumor tissues. In four cases with dysgerminomas, the DNA fingerprints of tumors were completely identical with those of the respective host mononuclear cells. The present results suggest that mature cystic teratomas of the ovary arise from germ cells arrested at various stages of meiosis, while immature teratomas are derived from postmeiotic germ cells. Malignant transformation may occur exclusively in the mature teratomas arising from postmeiotic germ cells. Dysgerminomas develop from premeiotic oogonia (primordial germ cells). Thus, DNA fingerprints are a useful and sensitive tool for identifying the pathogenesis of germ cell tumours.     

Treatment of malignant ovarian germ cell tumors: response to vincristine, dactinomycin, and cyclophosphamide (preliminary report)

From November 1971 to November 1975, 27 patients with malignant germ cell tumors of the ovary (excluding pure dysgerminoma and tumors containing trophoblastic elements) were treated with vincristine, dactinomycin, and cyclophosphamide; 12 patients received other therapy. Fourteen tumors were pure endodermal sinus tumors, two were embryonal carcinomas, 11 were mixed germ cell tumors and 12 were immature teratomas. Of 23 patients with surgically resected disease (Stages I-IIA) only seven have failed. Median follow-up for 16 patients remaining free of disease is 24.5 months. Restaging (second-look) laparotomies were done in 15 patients. Eight were negative. Fifteen of the patients had tumors with endodermal sinus elements. Six of these have failed. Of 16 patients with advanced disease (Stage IIB, III and recurrent), eight have responded to chemotherapy, eight have failed. Median follow-up period for those remaining free of disease is 26.5 months. Six have had negative second-look surgery and one had mature teratoma. Four of eight cases which contained endodermal sinus elements responded to chemotherapy and remain disease-free. Grade 3 hematologic toxicity was seen in eight patients, dose-limiting gastrointestinal toxicity in five patients, dose-limiting neurotoxicity in five patients.     

Pediatric central nervous system germ cell tumors: a review

Central nervous system (CNS) germ cell tumors (GCTs) represent approximately 3% of primary pediatric brain tumors and encompass a wide pathologic spectrum. CNS GCTs are most commonly located in the pineal and suprasellar regions of the brain and can be divided into major groups including germinomas and nongerminomatous GCTs (NGGCTs), with teratomas often considered a separate category. The clinical presentation varies by location and size, and it frequently includes endocrine abnormalities, visual changes, and signs of increased intracranial pressure. Neuroimaging studies cannot differentiate GCTs from other tumors, and therefore, the diagnosis usually requires histologic confirmation. The rare exceptions are the cases where characteristic elevations of tumor markers, including alpha-fetoprotein and/or beta-human chorionic gonadotropin are documented in the serum and/or cerebrospinal fluid. In these cases, the imaging findings along with the tumor marker elevation may be diagnostic in themselves without the need for tissue confirmation. Treatment and prognosis differ greatly between groups. Germinomas have a superior prognosis than NGGCTs. Five-year overall survival rates >90% were reported initially with the use of craniospinal irradiation. More recently, the use of chemotherapy in addition to radiation therapy has afforded the ability to decrease the dose and volume of radiation therapy without affecting survival rates. NGGCTs are less radiosensitive than germinomas, but the use of adjuvant chemotherapy has improved survival rates in this group as well. The standard management for CNS GCTs remains controversial. Treatment regimens aimed to improve progression-free and overall survival times are ongoing.     

Extrakraniale Keimzelltumoren des Kindes

Germ cell tumors are a heterogeneous group of embryonal tumors with different biological characteristics and localizations (gonadal and extragonadal). Treatment of malignant germ cell tumors takes place in risk-adapted multicentric and prospective trials of the German Society for Pediatric Oncology and Hematology for malignant germ cell tumours (MAKEI) and the International Society of Pediatric Oncology (SIOP), central nervous system (CNS) and germ cell tumor (GCT). In general germ cell tumors in infants and children carry a malignant potential. Therapy is based on surgery and neoadjuvant or adjuvant chemotherapy. Treatment and prognosis depend on tumor histology, age of the child and resectability of the tumor. The presented paper gives an overview on this topic.     

Apoptosis and proliferative activity in mature and immature teratomas of the mediastinum.

BACKGROUND: Mediastinal teratomas are the most frequent mediastinal germ cell tumor. Whereas mature teratomas are benign tumors, immature teratomas are malignant. The purpose of this study was to find characteristics that could be used to distinguish between the growth and prognosis of the two teratoma types. METHODS: Twenty-four mediastinal teratomas (18 mature and 6 immature) were examined for apoptosis by 3'-end labeling of DNA and stained immunohistochemically for proliferating cell nuclear antigen, Bcl-2, Bax, p53 protein, and alpha-fetoprotein (AFP) expression in formalin fixed, paraffin embedded specimens. RESULTS: AFP was expressed in both immature teratomas and mature teratomas. Whereas p53 protein was expressed by most teratomas, p53 gene mutation was observed in only one patient with an immature teratoma in which the same mutation occurred in all tumor tissue components tested. Bax protein expression was relatively diffuse in mature teratomas but was focally expressed in immature teratomas. Bcl-2 protein was expressed focally in both mature and immature teratomas. Although the proliferative index was significantly higher in immature teratomas compared with mature teratomas (P < 0.001), the apoptotic index (AI) was significantly higher in mature teratomas compared with immature teratomas (P < 0.05). All patients except one in this study remain alive and disease free after undergoing tumor resection. CONCLUSIONS: The relatively high AI in mature teratomas may be due to the overexpression of the p53 protein. In contrast, immature teratomas exhibited higher proliferative activity and lower rates of apoptosis, which may explain the more aggressive behavior of these tumors. However, patients with immature mediastinal teratomas have a good prognosis if the tumor is resected completely after chemotherapy.