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Primitive neuroectodermal tumors (PNET) belong to a family of pediatric neoplasms of the central nervous system (CNS) that are composed predominantly of primitive neuroepithelial cells. Among the different CNS PNET, those arising in the posterior fossa (i.e. medulloblastomas) are prototypical of this group of brain tumors. The basic cell biology of PNET is incompletely understood, but recent studies of human PNET biopsies and cell lines derived therefrom demonstrate that neoplastic cells in human PNET recapitulate many of the phenotypic properties of immature CNS neurons or their progenitors. Based on these findings, it has been possible to develop several animal models of human PNET that will enhance efforts to gain fundamental insights into the induction and progression of PNET. In addition, these model systems will enable emerging gene therapies to be targeted specifically for human PNET. Accordingly, this review summarizes current understanding of the cell biology of human PNET, particularly medulloblastomas, and it highlights the most salient features of representative in vivo model systems of human PNET that are relevant to future studies of these tumors.
Synovial sarcoma is a relatively common sarcoma in adults, which in its classic bimorphic form infrequently poses a diagnostic problem. Monomorphic spindled variants, as well as the less common poorly differentiated variants, may be confused with other soft-tissue sarcomas; the poorly differentiated variant (PDSS), in particular, may be histologically indistinguishable from other small, blue, round cell tumors, including primitive neuroectodermal tumors (PNETs). Detection of the synovial sarcoma-associated t(X;18) by either cytogenetic or molecular genetic approaches may be necessary to confirm the diagnosis of synovial sarcoma in difficult cases. We evaluated 10 cases of PDSS from eight patients using a panel of antibodies (including those to intermediate filament proteins, nerve-sheath associated markers, and neuronal and neuroectodermal associated markers) in order to better establish the immunophenotype of this tumor and to help distinguish it from the tumors with which it may be confused, particularly PNETs and high-grade malignant peripheral nerve sheath tumors (MPNSTs). Our results showed PDSS to have significant immunophenotypic overlap with both PNETs and MPNSTs. In most instances these three entities may be differentiated by a panel of antibodies that should include those to both low and high molecular weight cytokeratins, epithelial membrane antigen, type IV collagen, CD99, CD56, and S-100 protein. Our results also suggest that synovial sarcoma may be a tumor showing combined neuroectodermal and nerve sheath differentiation--perhaps because of translocation-associated expression of specific proteins--rather than a carcinosarcoma of soft tissues or a tumor of specialized arthrogenous mesenchyme.
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PURPOSE: The Ewing tumor (ET) family of peripheral primitive neuroectodermal tumors (pPNETs) are primitive small round-cell tumors (SRCTs) of the bone and soft tissue that occur predominantly in children and adolescents. However, pPNETs only rarely enter the differential diagnosis of bone and soft tissue SRCTs in adults. Recently, gene fusions between the EWS gene and different members of the ETS transcription factor family have been shown to occur in virtually all pPNETs and thus constitute a pathognomonic marker for this tumor subclass. The aim of the present study was to document EWS/ETS fusion gene expression in suspected pPNETs of adults as objective evidence for the existence of this tumor family in older patients. PATIENTS AND METHODS: The three contributing molecular diagnostic laboratories retrospectively compiled a cohort of all SRCT cases in which EWS/ETS gene fusions had been shown by molecular analysis. This cohort was surveyed for cases that occurred in patients aged 40 years or older, which were then analyzed for their clinical and pathologic features. RESULTS: Nine patients between 40 and 65 years of age were found to have tumors positive for EWS/ETS gene fusions. Standard histopathologic and clinical features of these cases, other than age, were similar to those of childhood pPNETs. Patients were initiated on appropriate therapy after molecular analysis confirmed the diagnosis of pPNET. CONCLUSION: Identification of an EWS/ETS gene fusion is useful in providing objective evidence of the diagnosis of pPNET in patients over the age of 40 years. This diagnosis should be considered in adults who present with bone and soft tissue SRCTs and appropriate biopsy specimens should be collected for molecular analysis at the time of diagnosis.
Primitive neuroectodermal tumors occur most frequently in bone and soft tissue but have been reported in other locations. Primary lung primitive neuroectodermal tumors without pleural or chest wall involvement are extremely rare. We present a case with immunohistochemical and ultrastructural studies and follow-up of the patient. An 18-year-old man presented with hemoptysis. Chest radiographs revealed a right middle lobe mass, and bronchoscopy showed an endobronchial tumor. The lesion was resected by middle lobectomy. After 2 years, a local recurrence was treated by pneumonectomy. The patient died after surgery. Histologically, the tumor was composed of uniform cells with round nuclei and scanty cytoplasm arranged in cohesive lobules with occasional rosette formation. Immunohistochemically, the tumor was positive for vimentin, CD99, neuron-specific enolase, and neurofilaments. Ultrastructural study revealed neurosecretory granules and cytoplasmic processes. Our case shows the value of immunohistochemistry and electron microscopy in the diagnosis of primitive neuroectodermal tumors in unusual locations.
Immunohistochemical lack of nuclear INI1 protein expression has been recently described as characteristic finding in atypical teratoid/rhabdoid tumors (AT/RTs), and has been suggested as useful marker to distinguish AT/RTs from other malignant pediatric central nervous system (CNS) tumors. In this study, we examined a large series of malignant pediatric CNS tumors to determine the immunohistochemical expression of INI1 protein in different malignant pediatric tumor entities. Archival paraffin-embedded biopsy specimens of 289 malignant pediatric CNS tumors including medulloblastomas, supratentorial primitive neuroectodermal tumors, glioblastomas, anaplastic astrocytomas, anaplastic ependymomas, choroid plexus carcinomas, germ cell tumors, and AT/RTs were analyzed immunohistochemically for expression of nuclear INI1 protein. Positive INI1 staining was observed in 263 tumors. Lack of INI1 protein was detectable in 26 tumors. Seventeen of the 26 tumors showed morphologically characteristic features of AT/RTs, whereas 9 embryonal tumors did not display rhabdoid features. Tumors without rhabdoid phenotype but lack of INI1 showed an aggressive clinical course and poor response to conventional treatment regimens. In summary, immunohistochemical expression of INI1 protein is lacking in tumors displaying characteristic morphologic features of AT/RT. Furthermore, a certain number of embryonal tumors without rhabdoid features but lack of INI1 protein and aggressive biologic behavior can be detected. We conclude that INI1 protein analysis should be routinely performed in all malignant pediatric embryonal CNS tumors to detect cases with lack of INI1 protein, because patients with these tumors are likely to benefit from intensified treatment.
Primitive neuroectodermal tumors (PNET) represent about 25% of primary central nervous system tumors in childhood, but congenital PNETs are rare. Cytogenetic studies and studies on molecular pathology have identified several genetic alterations in medulloblastoma, but molecular investigations on supratentorial PNETs are infrequent. We present a male newborn with a large congenital PNET of the right cerebral hemisphere and the molecular analysis of the tumor. Tumor tissue was investigated by routine histology and immunohistochemistry. Fluorescence in-situ hybridization was carried out on native tumor tissue to investigate deletions on chromosome 17p and to analyze c-Myc or N-Myc amplifications. Histologic examination revealed a primitive neuroectodermal tumor with massive extension covering almost the entire right hemisphere. Genetic analysis of the native tumor tissue of our patient excluded a deletion of chromosome 17p. An amplification of the c-Myc or N-Myc oncogene was absent using fluorescence in-situ hybridization. Despite unremarkable genetic analysis in our case prognosis was poor, suggesting that there are additional, yet unknown constitutional genetic aberrations in the pathogenesis of congenital supratentorial PNET.
Primitive neuroectodermal tumor is an extraordinarily rare primary tumor in the kidney and can be mistaken for a variety of other round cell tumors. It is important to recognize each of these entities, because each carries unique therapeutic and prognostic implications. However, accurate diagnosis of these tumors is hindered by their significant morphologic overlap and complicated by their rarity. These neplasm are highly aggressive that tend to recurence and to metastatize. Standard therapy combining surgery, chemotherapy, radiation and genetic therapy. We report a case of primitive neuroectodermal tumor of the kidney in a 50 year old female patient.
PURPOSE: To determine whether age at diagnosis influences the behavior of Ewing's sarcoma and primitive neuroectodermal tumor (PNET). PATIENTS AND METHODS: We reviewed the clinical features, treatment, and outcome of 59 consecutive patients with Ewing's sarcoma and PNET treated on the Adult Sarcoma Unit at our institution from 1980 to 1995. RESULTS: The 37 male and 22 female patients had a median age of 24 years. Lower limb was the most common primary tumor site. Fifteen patients had nonmetastatic tumor less than 100-mL volume, 27 had nonmetastatic disease greater than 100-mL volume, and 17 had evidence of metastatic disease at presentation. The origin of the primary tumor was soft tissue in 28 cases, bone in 30, and uncertain in one. The Kaplan-Meier estimate of 5-year overall survival (OS) in all patients was 38% and of progression-free survival (PFS), 27%. When patients with metastatic disease at presentation were excluded, these figures increased to 52% and 34%, respectively. Bulk of disease at presentation and response to primary treatment were statistically highly significant predictors of both PFS and OS. Age and tissue of origin of the tumor did not influence outcome. CONCLUSION: The behavior of Ewing's sarcoma and PNET in adults is no different from its behavior in children. We feel the way forward in the treatment of adults with Ewing's sarcoma and PNET is for them to be included in the current multicenter trials of multidisciplinary treatment directed at children.
Primitive neuroectodermal tumors ( PNET ) of the central nervous system in children are rare, highly malignant, cystic, and sometimes calcific, and hemorrhagic tumors sharply demarcated from adjacent brain. Microscopically they consist of small predominantly undifferentiated dark cells with neuronal, glial, and mesenchymal elements. We have recently diagnosed and treated five children with PNET . We will review their case histories as well as summarize the previous 133 reported cases with reference to presenting complaints, tumor location, neurodiagnostic studies, and the retrospective results of four treatment programs: 1) surgery alone; 2) surgery and radiation therapy; 3) surgery, radiation therapy, and chemotherapy at time of recurrence; and 4) surgery, radiation therapy, and chemotherapy at onset.
PURPOSE: Supratentorial primitive neuroectodermal tumor (PNET) accounts for 2-3% of all pediatric brain tumors. We retrospectively reviewed all supratentorial PNET cases treated with radiotherapy (RT) at our institutions. METHODS AND MATERIALS: A total of 25 patients (17 males and 8 females, median age 9 years) were treated with RT between 1980 and 2001. The primary site location was the pineal region in 7 (28%), temporal lobe in 5 (20%), thalamus in 5 (20%), frontal lobe in 4 (16%), parietal lobe in 2 (8%), and suprasellar region in 2 (8%). Five patients (20%) had neuraxis dissemination (M+ disease) at initial diagnosis. The RT treatment volumes were craniospinal (CS) in 17 (68%), whole brain (WB) followed by a boost in 2 (8%), and primary site (PS) alone in 6 (24%). The median dose to the primary site was 54 Gy (range, 31-55.8 Gy). The median dose to patients receiving WB and spinal fields was 36 Gy (range, 23.4-39.6 Gy). Sixteen patients (64%) received chemotherapy; the most common type was the "8 in 1" chemotherapy regimen in 9 children. The median follow-up of surviving patients was 70 months (range, 34-251 months). RESULTS: The 5-year and 10-year progression-free survival rate was 36% and 27%, respectively, and the median time to progression was 22 months. The 5-year and 10-year progression-free survival rate was 47.1% and 47.1% for those receiving CSRT and 12.5% and 0% for those receiving WBRT or PSRT, respectively. The 5-year and 10-year progression-free survival rate for those with M0 disease was 40.0% and 30.0%, respectively; for those with M+ disease, the corresponding figures were 20.0% and 0%. On multivariate analysis, only M status (p = 0.01) and RT volume (p = 0.02) were statistically significant according to the Cox proportional hazards model. The primary site control rate at 5 and 10 years was 62%. Failure at nontreated neuraxis sites was a common cause of progression in patients receiving WBRT or PSRT, as seen in 6 (75%) of 8 cases. Of the 17 patients undergoing CSRT, 8 had no recurrence. Eight of the nine CSRT relapses had a leptomeningeal component. Four (80%) of 5 M+ children and 4 (33%) of 12 M0 children who underwent CSRT developed recurrence in the neuraxis (p = 0.1, Fisher's exact test). CONCLUSION: The craniospinal axis is the standard volume that needs to be treated in supratentorial PNET. Leptomeningeal dissemination was the main obstacle for cure even in patients receiving CSRT, regardless of M status.
Medulloblastoma and primitive neuroectodermal tumors (PNETs) are the most common malignant brain tumors in children. The concern for late sequelae of neuraxis irradiation and the obligation to improve disease-free survival in children who harbor malignant brain tumors has led to the additional provision of systemic chemotherapy to standard- and reduced-dose radiotherapy, as well as to the evaluation of alternate modes of radiotherapy delivery. Analysis of evidence has suggested that chemotherapy has an impact on length of survival in children with medulloblastoma and PNETs. The question remains as to whether chemotherapy combined with reduced-dose radiotherapy provides greater benefit than standard-dose radiotherapy alone, and which subset of children the treatment most benefits. Also unanswered is the question of whether chemotherapy can serve as the primary treatment in infants with these lesions. In an attempt to help answer these questions, the authors review the major chemotherapy and radiotherapy trials for newly diagnosed patients and those with recurrent medulloblastoma and PNETs.
Primitive neuroectodermal tumors (PNETs) of the central nervous system, including medulloblastomas (PNET/MB), are the most common malignant brain tumor of childhood. These tumors often express proteins characteristic of glial differentiation (glial fibrillary acidic protein, GFAP), neuronal differentiation (neurofilament proteins, NFPs), and/or photoreceptor differentiation (retinal-S antigen). To identify biological factors of prognostic significance in PNETs, the expression of glial, neuronal, or photoreceptor antigens was evaluated in the tumor specimens of 86 patients with PNETs by immunohistochemistry after microwave antigen enhancement. Patterns of differentiation were then compared with patient relapse-free survival. Multivariate analysis of PNET immunohistochemistry and clinical variables indicated GFAP expression conferred a 6.7-fold greater risk of relapse than tumors that did not express GFAP or NFPs. Increased risk of relapse was directly related to the amount of GFAP expression. Tumors exhibiting clumps or sheets of GFAP-staining cells were associated with a 3.0-fold increased risk of relapse compared with tumors that did not express GFAP, irrespective of immunohistochemical evidence of other differentiation, while scattered GFAP staining was not associated with increased risk of relapse. These findings indicate that expression of GFAP in PNETs has prognostic power comparable with the most significant clinical factors currently used to predict clinical outcome.
Primitive neuroectodermal tumors (PNETs), including medulloblastoma (PNET/MB) and supratentorial PNET (sPNET), are the most common malignant brain tumors of childhood. The stabilization of telomere lengths by telomerase activation is an important step in carcinogenesis and cell immortalization. Epigallocatechin gallate (EGCG), the major polyphenol in green tea, is a telomerase inhibitor with antiproliferative and anticarcinogenic effects against different types of cancer. In this study, we used real-time reverse transcriptase-polymerase chain reaction to measure the mRNA expression of the human telomerase reverse transcriptase (hTERT) in 50 primary PNET samples (43 PNET/MB, 7 sPNET), 14 normal human brain samples, and 6 human PNET cell lines. Compared to normal human cerebellum, 38/50 (76%) primary PNET samples had >or= 5-fold upregulated hTERT mRNA expression. We then examined PNET cell lines for telomerase activity using a quantitative telomeric repeat amplification protocol (TRAP), and for telomere length using terminal restriction fragment analysis. While a positive correlation between hTERT mRNA expression and telomerase activity was detected in PNET cell lines, no correlation was found between telomerase activity and telomere length. Treatment of PNET cell lines with EGCG resulted in a dose-dependent inhibition of telomerase activity at micromolar levels. Although EGCG displayed strong proliferation inhibitory effects against TRAP-positive PNET cell lines, it had no significant effect against TRAP-negative D425 cells. These results provide evidence for a possible role of telomerase in the pathogenesis of most PNETs and indicate that subsets of PNETs maintain telomere length by alternative mechanisms. Inhibition of telomerase function represents a novel experimental therapeutic strategy in childhood PNETs that warrants further investigation.
Germ-line and somatic mutations of the hSNF5/INI1 gene have been reported in atypical teratoid/rhabdoid tumors (AT/RTs) of the brain, consistent with its role as a tumor suppressor gene. In the present study, we determined the frequency of deletions and mutations of INI1 in 52 children whose original diagnosis was medulloblastoma (MB) or primitive neuroectodermal tumor (PNET) of the central nervous system. Mutations were detected in DNA isolated from four tumors, all from children less than 3 years of age at diagnosis. Two of the four were reviewed and reclassified as atypical teratoid tumor, whereas there was insufficient material to establish this diagnosis in the two remaining cases. The relatively low frequency of mutations, even in a large series of infants, suggests that loss of sequences from chromosome 22 and/or mutations of INI1 do not account for the poor prognosis of children with MB or PNET who are less than 3 years of age at diagnosis. Nevertheless, chromosome 22 deletion and INI1-mutation analysis of infants with MB/PNET should be considered for all children who are less than 1 year of age. Detection of these mutations suggests that the child has an AT/RT, rather than a MB/PNET, a finding with important prognostic value.
This study reports on the specific expression of the MIC2 gene, a pseudoautosomal gene located on the short arms of the X and Y chromosomes, on Ewing's sarcoma (ES) and peripheral primitive neuroectodermal tumor (pPNET) cells. The gene product, a cell membrane protein, is recognized by the newly established monoclonal antibody (MoAb) HBA-71 and the previously described MoAb 12E7 and RFB-1. Furthermore, the reaction pattern of the MIC2 antibodies, especially HBA-71, with normal tissues and a great number of benign and malignant tumors (70 different tumors, 199 tumor samples), as well as the correlation between the specific chromosomal aberrations, i.e., the t(11;22) and the del(22) and the expression of this antigen, are demonstrated. Both ES and pPNET cells express the MIC2 gene in very high amounts, which represents a highly selective and almost unique feature of these cells, making an assignment of these tumors in one entity even more likely. The MIC2 antibodies are of great value for clinical and research purposes.