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PubMed2001

Pathology of pineal region tumors.

Various histological types of tumors arise in the pineal region. The most common tumors are pineal parenchymal tumors and germ cell tumors. Pineal parenchymal tumors are divided into pineocytoma, pineal parenchymal tumor with intermediate differentiation and pineoblastoma. Pineocytomas are well-differentiated tumors and retain the morphological and immunohistochemical features of pineal parenchymal cells. Lobular architectures and pineocytomatous rosettes are also typical features. In contrast, pineoblastomas are embryonal tumors resembling primitive neuroectodermal tumors (PNET). However, pineoblastomas are distinct from PNET in other sites due to their exhibiting photosensory differentiation including Flexner-Wintersteiner rosettes and fleurettes. Although pineal cysts are tumor-like lesions, and not true neoplasms, they are occasionally difficult to distinguish from pineocytoma and astrocytoma. From the therapeutic aspect, a precise differential diagnosis is critical. The pineal region is the most common site of the brain in which germ cell tumors occur. Germinoma, teratoma, embryonal carcinoma, yolk sac tumor and choriocarcinoma are encountered, and the latter three types of tumors usually constitute elements of mixed germ cell tumors. The morphological and immunohistochemical features of intracranial germ cell tumors are very similar to those of gonadal germ cell tumors, although there are some differences in germinoma. Pineal germinoma may exhibit carcinomatous differentiation. Other types of tumors are occasionally observed, including fibrillary and pilocytic astrocytoma, glioblastoma, ependymoma, melanoma, meningioma and so on. Metastatic pineal tumors are also rare. The most common site of origin for pineal metastasis is the lung.

Brain Neoplasms↗
PubMed2002

Supratentorial embryonal tumors in children under 5 years of age: an SFOP study of treatment with postoperative chemotherapy alone.

BACKGROUND: To determine the effectiveness of multiagent chemotherapy as sole post-operative treatment of supratentorial central nervous system (CNS) embryonal tumors in young children. PROCEDURE: The data of 25 children under 5 years of age diagnosed with supratentorial embryonal tumors (17 primitive neuroectodermal tumors, four pinealoblastomas, and four medulloepitheliomas) treated exclusively by postoperative chemotherapy (CT) between 1990 and 1997 were reviewed. RESULTS: Fifteen tumors were hemispheric and 10 were deeply seated. Four children presented with disseminated leptomeningeal disease. Total resection was performed in nine patients, subtotal in 9, partial in 3, and a diagnostic biopsy only in 2. Two children did not undergo surgery. Twenty-four children relapsed with a median time of 5.5 months. The median overall survival was 12 months, and the 2-, and 5- year survivals were 30 and 14%, respectively. The 2- year disease-free survival was 4%. There was a significantly worse prognosis in patients undergoing incomplete resection and in the group with deeply situated tumors. Four relapses were treated by second surgery followed by high-dose chemotherapy and radiotherapy. Two of them remain in CR2, and all these children are free of late sequelae. CONCLUSIONS: CT alone failed to maintain disease-free survival in most of the children, although, disease progression was delayed to some extent. Children under 5 years with supratentorial embryonal tumors should undergo total surgical resection if possible.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Extraskeletal Ewing sarcoma in a 77-year-old woman.

Extraskeletal Ewing sarcoma (EES) is a rare soft tissue tumor that is morphologically indistinguishable from Ewing sarcoma of bone. It is usually found in young people, but several cases have occurred in patients older than 50 years. The differential diagnoses include other small, blue round cell tumors (SBRCTs) and other members of the Ewing family of tumors such as the primitive neuroectodermal tumor. We present a case of EES in the left inguinal region of a 77-year-old woman. The tumor was distinguished from other SBRCTs by lack of immunoreactivity for epithelial, lymphoid, vascular, neuroendocrine, neural, histiocytic, and muscle markers. Primitive neuroectodermal tumor was excluded because of the lack of neural differentiation by histologic analysis, immunohistochemistry, and electron microscopy. Extraskeletal Ewing sarcoma was confirmed by characteristic features on histologic analysis, histochemistry, immunohistochemistry, and electron microscopy and by the presence of the t(11;22)(q24;q12) fusion transcript detected by reverse transcriptase-polymerase chain reaction. This case serves to remind the reader that EES is not a tumor that occurs exclusively in young patients.

Aged↗
PubMed2000

Association of EWS-FLI1 type 1 fusion with lower proliferative rate in Ewing's sarcoma.

The Ewing's sarcoma (ES) family of tumors, including peripheral neuroectodermal tumor (PNET), is defined genetically by specific chromosomal translocations resulting in fusion of the EWS gene with a member of the ETS family of transcription factors, either FLI1 (90-95%) or ERG (5-10%). A second level of molecular genetic heterogeneity stems from the variation in the location of the translocation breakpoints, resulting in the inclusion of different combinations of exons from EWS and FLI1 (or ERG) in the fusion products. The most common type of EWS-FLI1 fusion transcript, type 1, is associated with a favorable prognosis and appears to encode a functionally weaker transactivator, compared to other fusion types. We sought to determine whether the observed covariation of structure, function, and clinical course correlates with tumor cell kinetic parameters such as proliferative rate and apoptosis, and with expression of the receptor for insulin-like growth factor I (IGF-1R). In a group of 86 ES/PNET with defined EWS-ETS fusions (45 EWS-FLI1 type 1, 27 EWS-FLI1 non-type 1, 14 EWS-ERG), we assessed proliferation rate by immunostaining for Ki-67 using MIB1 antibody (n = 85), apoptosis by TUNEL assay (n = 66), and IGF-1R expression by immunostaining with antibody 1H7 (n = 78). Ki-67 proliferative index was lower in tumors with EWS-FLI1 type 1 than those with non-type 1 EWS-FLI1, whether analyzed as a continuous (P = 0.049) or categorical (P = 0.047) variable. Logistic regression analysis suggests that this association was secondary to the association of type 1 EWS-FLI1 and lower IGF-1R expression (P = 0.04). Comparing EWS-FLI1 to EWS-ERG cases, Ki-67 proliferative index was higher in the latter (P = 0.01, Mann-Whitney test; P = 0.02, Fisher's exact test), but there was no significant difference in IGF-1R. TUNEL results showed no significant differences between groups. Our results suggest that clinical and functional differences between alternative forms of EWS-FLI1 are paralleled by differences in proliferative rate, possibly mediated by differential regulation of the IGF-1R pathway.

Adolescent↗
PubMed1990

A new human highly tumorigenic neuroblastoma cell line with undetectable expression of N-myc.

A peculiar human cell line (GI-ME-N) derived from the metastatic bone marrow of a 2-yr-old patient with stage IV neuroblastoma (NB) was extensively characterized. Cell-type-specific markers, tumorigenicity in nude mice, morphology, cytogenetics, and amplification/expression of the N-myc gene were evaluated. All metaphases presented the typical 1p deletion. Surface markers specific for NB cells, vimentin, and neurofilament proteins were all clearly detectable with immunofluorescence and/or western blot procedures. Moreover, it was found that GI-ME-N cells did not express N-myc oncogene or HLA class 1 antigens, and were not classified as peripheral neuroectodermal tumor cells. However, extremely short latency and survival times, comparable to peripheral neuroectodermal tumor cells, were observed in nude mice grafted with GI-ME-N. In addition, no correlations were observed in tumorigenicity of N-myc amplified (IMR32) versus unamplified (SK-N-SH GI-ME-N) human NB cell lines in nude mice. We conclude that N-myc amplification/expression do not correlate with the aggressiveness of human NB in athymic animals, which is not always explained by the peripheral neuroectodermal tumor cell nature of the malignant cells, either.

Animals↗
PubMed2002

Role of the aspartyl-asparaginyl-beta-hydroxylase gene in neuroblastoma cell motility.

Aspartyl (asparaginyl) beta-hydroxylase (AAH) is overexpressed in various malignant neoplasms, and high levels of immunoreactivity mainly occur in infiltrating or metastasized tumors. In addition, AAH is abundantly expressed in normally invasive placental trophoblastic cells. These observations led to the hypothesis that AAH may have a role in motility and aggressive behavior of tumor cells. The present study demonstrates that AAH is overexpressed in primary human malignant neuroectodermal tumors, including medulloblastomas and neuroblastomas, and that AAH expression is at a low level or undetectable in the normal mature brain. In the Sy5y neuroblastoma cell line, endogenous expression of the approximately 86-kd AAH protein was demonstrated by Western blot analysis, and immunoreactivity predominantly localized to the cell surface by immunocytochemical staining and FACS analysis. Sy5y cells that were stably transfected with the human AAH cDNA had increased levels of proliferating cell nuclear antigen and Bcl-2, and reduced levels of p21/Waf1 and p16. In addition, increased AAH expression enhanced Sy5y cell motility, whereas antisense oligodeoxynucleotide inhibition of AAH significantly reduced Sy5y cell motility and increased the levels of p21/Waf1 and p16. The findings suggest that AAH overexpression contributes to the malignant phenotype of neuroectodermal tumor cells by increasing motility and enhancing proliferation, survival, and cell cycle progression. Because AAH expression is at a low level or undetectable in normal brain, the AAH gene may be a target for treating primitive neuroectodermal tumors.

Antibodies, Monoclonal↗
PubMed2005

Emergency management of severe right ventricular inflow obstruction secondary to a metastatic cardiac tumor.

We report the case of a 21-year-old female with previous history of primitive neuroectodermal tumor of the anterior abdominal wall who developed severe manifestations of right heart failure due to a mass obliterating the right ventricular cavity. She underwent emergent resection of the mass with histopathologic confirmation of metastatic neuroectodermal tumor. To the best of our knowledge, this is the first case of emergent surgical excision of a metastatic cardiac tumor of primitive neuroectodermal origin.

Abdominal Neoplasms↗
PubMed1997

Expression of type I interferon receptor in solid tumors of childhood.

Interferon alpha (IFN alpha) is used as an antineoplastic agent, both in hematopoietic malignancies and in solid tumors, because of its immunomodulatory action and direct antitumor activity. IFN alpha binds to specific cell-surface receptors that mediate its biologic activity. We studied the expression of IFN alpha receptors in pediatric solid tumors by use of the monoclonal antibody IFNaR3, which specifically recognizes the alpha subunit of the IFN Type I receptor. In three cell lines derived from those tumors, we determined the structure of the receptors by affinity cross-linking and immunoprecipitation techniques, and we determined their ability to mediate an antiproliferative effect. All of the tumor specimens studied by immunocytochemical analysis, including neuroblastomas, primitive neuroectodermal tumors, and rhabdomyosarcomas, stained positive for the IFN alpha receptor antibody, although in some cases immunoreactivity was weak. The three cell lines, derived from a neuroblastoma, a primitive neuroectodermal tumor, and a Ewing's sarcoma, respectively, showed the same pattern of IFN alpha receptor expression, both by affinity crosslinking and immunoprecipitation assays. Treatment with IFN alpha of those cell lines induces growth inhibition in vitro. These results suggest that IFN Type I receptor might be expressed in most solid tumors of childhood and that its structure is identical to the receptor expressed by the majority of hematologic malignancies.

Adolescent↗
PubMed2004

The Ews/Fli-1 fusion gene changes the status of p53 in neuroblastoma tumor cell lines.

One hallmark of Ewing's sarcoma/peripheral neuroectodermal tumors is the presence of the Ews/Fli-1 chimeric oncogene. Interestingly, infection of neuroblastoma tumor cell lines with Ews/Fli-1 switches the differentiation program of neuroblastomas to Ewing's sarcoma/peripheral neuroectodermal tumors. Here we examined the status of cytoplasmically sequestered wt-p53 in neuroblastomas after stable expression of Ews/Fli-1. Immunofluorescence revealed that in the neuroblastoma-Ews/Fli-1 infectant cell lines, p53 went from a punctate-pattern of cytoplasmic sequestration to increased nuclear localization. Western blot analysis revealed that PARC was down-regulated in one neuroblastoma cell line but not expressed in the second. Therefore, decreased PARC expression could not fully account for relieving p53 sequestration in the neuroblastoma tumor cells. Neuroblastoma-Ews/Fli-1 infectant cell lines showed marked increases in p53 protein expression without transcriptional up-regulation. Interestingly, p53 was primarily phosphorylated, without activation of its downstream target p21(WAF1). Western blot analysis revealed that whereas MDM2 gene expression does not change, p14(ARF), a negative protein regulator of MDM2, increases. These observations suggest that the downstream p53 pathway may be inactivated as a result of abnormal p53. We also found that p53 has an extended half-life in the neuroblastoma-Ews/Fli-1 infectants despite the retention of a wild-type sequence in neuroblastoma-Ews/Fli-1 infectant cell lines. We then tested the p53 response pathway and observed that the neuroblastoma parent cells responded to genotoxic stress, whereas the neuroblastoma-Ews/Fli-1 infectants did not. These results suggest that Ews/Fli-1 can directly abrogate the p53 pathway to promote tumorigenesis. These studies also provide additional insight into the relationship among the p53 pathway proteins.

Cell Line, Tumor↗
PubMed1996

[Pathology of Ewing sarcoma].

Ewing's sarcoma is a very rare tumor which has, however, attracted much oncological interest since the dramatic improvement of its prognosis under chemotherapy. Its histogenesis has been discussed controversially for a long time, including a possible origin in immature reticulum, myogenous, endothelial and undifferentiated mesenchymal cells. Repeated reports have also suggested a possible neuroectodermal genesis. Convincing arguments, however, have only been brought forward during recent years, since it was found that Ewing's sarcoma and malignant peripheral neuroectodermal tumor share a common chromosome translocation 11;22. In the meantime this hypothesis has been strengthened by numerous cell biological analyses. There seems to be no clear border between Ewing's sarcoma and malignant peripheral neuroectodermal tumors with definite neural differentiation. Histological differential diagnosis of Ewing's sarcoma has been improved by immunohistological methods. In most cases, they can be distinguished from lymphoma (leucocyte common antigen, B and T markers) and embryonal rhabdomyosarcoma (muscle specific actin, desmin) without problems. Apart from that, it is possible nowadays to obtain antibodies against the MIC 2-protein, which is preferably expressed in Ewing sarcoma. The diagnostics of Ewing's sarcoma and the malignant peripheral neuroectodermal tumor have considerably been enriched by the fact that the specific chromosome translocation t(11;22) can be proved molecular biologically. In contrast to the cytogenetic evidence, it is not necessary to establish cell cultures.

Biomarkers, Tumor↗
PubMed2000

Embryonal tumors in the adult population: implications in therapeutic planning.

The natural history of neuroectodermal tumors is still debated as far as prognostic factors are concerned; the same uncertainty applies to the optimal radiotherapy schedule and even more to the presumptive additive effect of chemotherapy. The rarity of these tumors and the heterogeneity of management make interpretation of literature data also more difficult. We evaluated clinical course in a cohort of 39 patients, including 31 with medulloblastoma (MB) and 8 with primitive neuroectodermal tumors (PNET). All patients were treated with radiotherapy, a standardized chemotherapy protocol including PCV scheme, and a second-line chemotherapy with cisplatin and etoposide (VP16) at recurrence. In 27 patients, intrathecal chemotherapy was also delivered. Median follow-up was 10.8 years. Overall, PNET had a worse outcome as compared to MB: median survival times were 42.8 vs. 92.6 months, respectively (p = 0.05). At 5 years, 45% of MB patients are alive. No significant difference in disease-free period was found between patients of different age, desmoplastic variant, tumor localization, or extent of surgery. Patients considered to be "high risk" had a significantly shorter disease-free period as compared with low-risk patients (27 vs. 54.7 months, p = 0.04). Systemic or intrathecal chemotherapy did not influence progression-free survival (PFS). However, in the majority of chemotherapy-treated patients, a low-dose craniospinal radiotherapy was also delivered. This combination of treatments may have avoided the expected increased percentage of failure. Moreover, more than half of recurrent patients had a partial response to chemotherapy that extended survival for approximately 3 years. Repeated surgery and chemotherapy at recurrence favorably influenced survival time.

Adult↗
PubMedDate not supplied

Extracellular matrix of small round cell tumors of childhood: an immunohistochemical study of 67 cases.

Sixty-seven childhood tumors were studied immunohistochemically for the extracellular matrix element type IV collagen, laminin, and fibronectin. Tumors included Ewing's sarcoma, primitive neuroectodermal tumor, small cell osteosarcoma, neuroblastoma or ganglioneuroblastoma, rhabdomyosarcoma, and lymphoma. It was found that small cell osteosarcoma was often positive for fibronectin but not type IV collagen or laminin, a new observation. In the lymphomas, matrix proteins were rarely found. Ewing's sarcoma was variably positive for type IV collagen and laminin, but fibronectin was absent. Extracellular laminin and fibronectin were found in one of two cases of primitive neuroectodermal tumor. In neuroblastoma and ganglioneuroblastoma, the matrix components were rarely found. These results, discrepant with findings in cultured cells, may reflect the altered capacity of tumors to produce these proteins in vitro, which suggests that caution should be exercised in drawing conclusions regarding the nature or histogenesis of tumors from data obtained with cultured tumor cells. Embryonal rhabdomyosarcoma frequently contained all matrix elements in the extracellular space and in a dotlike pattern in the cytoplasm; alveolar rhabdomyosarcoma rarely contained these proteins and never exhibited the dotlike pattern. The frequent finding of matrix proteins in embryonal rhabdomyosarcoma but only rarely in alveolar rhabdomyosarcoma and the unique immunostaining pattern in embryonal rhabdomyosarcoma may prove to be a useful adjunct in the diagnosis of childhood tumors.

Adolescent↗
PubMed2001

Flt-3 and its ligand are expressed in neural crest-derived tumors and promote survival and proliferation of their cell lines.

Flt-3 ligand (FL) is a cytokine that promotes the survival, proliferation, and differentiation of hematopoietic progenitors in synergy with other growth factors, such as stem cell factor. Previously we have demonstrated that stem cell factor and its receptor c-kit are expressed in neural crest-derived tumor cells and that a c-kit block induces their apoptosis. Here we have evaluated the expression of flt-3 and its ligand in 12 neuroectodermal tumor cell lines from neuroblastoma (NB), neuroepithelioma (NE), Ewing sarcoma (ES), and peripheral neuroectodermal tumor (PNET) and in 38 biopsies: 19 from NB and 19 from ES and PNET. RT-PCR demonstrated the expression of flt-3 and FL in all lines. Coexpression was observed in 42% of NB and in 74% of ES and PNET biopsies. Flow cytometry confirmed the presence of membrane and cytoplasmic flt-3 and membrane FL in all lines, whereas soluble FL protein was not measurable in their supernatants. Microphysiometric demonstration of acidification of the medium provided evidence of the specific response of cell lines to FL stimulation. Specific flt-3 phosphorylation after FL treatment was also demonstrated by Western blotting analysis. In cells growing in RPMI plus 1% fetal calf serum, FL revealed a significant proliferating activity, more evident in NB and NE lines (mean increase of viable cells, 73 +/- 26% after 1 day). Treatment with flt-3 antisense oligonucleotides significantly inhibited cell growth. FL also displayed an antiapoptotic activity: after a 12-hour culture in the presence of 0.1% fetal calf serum, FL caused a 50% reduction of apoptotic cells. These results provide further evidence that neuroectodermal and hematopoietic cells share common regulatory pathways, and could be of interest in the clinical management of neuroectodermal tumors.

Base Sequence↗
PubMed1986

Detection of N-myc oncogene expression in human neuroblastoma by in situ hybridization and blot analysis: relationship to clinical outcome.

We studied N-myc oncogene expression in 13 human neuroectodermal tumors and one teratoma by in situ hybridization. In four of six neuroblastomas, there was increased N-myc expression (15 to 49% of the cells). Many of the primitive neuroblastic cells had an increase of N-myc RNA not observed in the larger, more differentiated cells. Two neuroblastomas matured to ganglioneuromas; no biopsies performed during this progression expressed increased N-myc RNA. Three ganglioneuroblastomas, two tumors presenting as ganglioneuromas, a cerebral neuroectodermal tumor, a neurofibrosarcoma, and the teratoma did not have increased N-myc expression. The data obtained by in situ hybridization correlated well with data obtained by blot analysis. Neuroblastomas/ganglioneuroblastomas with a favorable course did not have appreciable elevation of N-myc expression over 10 to 77 mo of follow-up; thus N-myc may not be involved in the maintenance of the neoplastic state. However, such tumors with a fatal outcome 2 to 14 mo after diagnosis usually had elevated N-myc expression. These findings suggest a relationship between elevated levels of N-myc RNA and poor prognosis.

Brain Neoplasms↗
PubMed1995

Toxicity and efficacy of carboplatin and etoposide in conjunction with disruption of the blood-brain tumor barrier in the treatment of intracranial neoplasms.

CARBOPLATIN AND ETOPOSIDE have been investigated in preclinical studies and a limited toxicity study in 13 patients; these studies have established carboplatin and etoposide as a tolerable combination when administered with blood-brain barrier disruption. The studies also found a predictable dose-limiting toxicity of myelosuppression. Subsequently, a broad efficacy trial of this regimen was carried out. A total of 34 patients, ranging in age from 7 to 72 years, underwent a combination chemotherapy regimen of carboplatin (200 mg/m2 administered intra-arterially) and etoposide (200 mg/m2 administered intravenously) administered with blood-brain barrier disruption on each of 2 consecutive days every 28 days. The diagnoses included glioblastoma multiforme (n = 3), malignant astrocytoma (n = 8), malignant astrocytoma-oligodendroglioma (n = 1), primitive neuroectodermal tumor (n = 4), disseminated germ cell tumor of the central nervous system (CNS) (n = 6), CNS lymphoma (n = 7), and metastatic carcinoma (n = 5). The major toxicity observed in patients treated with multiple courses of this regimen was the expected reversible myelosuppression and an unexpected, irreversible high-frequency hearing loss. Of these 34 patients, 22 had measurable disease, and 9 radiographic responses (50% or more decrease in enhancing tumors) were observed in these patients. Carboplatin and etoposide with blood-brain barrier disruption is an active regimen in the treatment of malignant astrocytomas and has shown dramatic responses in primitive neuroectodermal tumors and CNS lymphoma. Additionally, the durability of responses in patients with disseminated CNS germ cell tumors is encouraging. However, such therapy is associated with unexpected high-frequency hearing loss; even so, on the basis of the favorable responses in patients with primitive neuroectodermal tumors, germ cell tumors, and lymphomas, the study of this regimen for those tumors is being extended in a multiinstitutional trial that also includes cytoxan to further evaluate the potential enhanced drug delivery.

Adolescent↗