Cerebral Primitive Neuroectodermal Tumors Research Articles

Is Ovarian Tissue Transplantation Safe in Patients with Central Nervous System Primitive Neuroectodermal Tumors?

The risk of reseeding malignancy harbored in cryopreserved and transplanted ovarian tissue has been a source of concern. This study aimed to determine the potential relationship between frozen–thawed ovarian tissue transplantation and primary cancer recurrence. Three patients with cerebral primitive neuroectodermal tumors (PNET) were included in this study. One woman gave birth to three healthy babies following reimplantation of her cryopreserved ovarian tissue, but subsequently died due to cancer relapse six years after ovarian tissue transplantation. The second subject died from progressive cancer, while the third is still alive and awaiting reimplantation of her ovarian tissue in due course. Frozen ovarian cortex from all three patients was analyzed and xenotransplanted to immunodeficient mice for five months. Main outcomes were the presence of cancer cells in the thawed and xenografted ovarian tissue at histology, immunostaining (expression of neuron-specific enolase and glial fibrillary acidic protein (GFAP)), and reverse-transcription droplet digital polymerase chain reaction (RT-ddPCR) (levels of enolase 2 and GFAP). In conclusion, no malignant cells were detected in ovarian tissue from patients with PNET, even in those who experienced recurrence of the disease, meaning that the risk of reseeding cancer cells with ovarian tissue transplantation in these patients can be considered low.

Primary extraosseous intradural spinal Ewing’s sarcoma: report of two cases

Two cases of primary extraosseous intradural spinal Ewing's sarcoma are reported with a review of the current literature. This rare neoplasm shares features with cerebral primitive neuroectodermal tumors, complicating a correct diagnosis. Gross total resection seems to be the main treatment, although adjuvant therapies could improve the prognosis. In case 1, a 56-year-old man presented with cauda equina syndrome. MRI showed an intradural tumor from L4 to S2. An emergency laminectomy was performed with gross total resection of a hemorrhagic tumor, followed by adjuvant treatment. In the second case, a 25-year-old female developed leg and lumbar pain. MRI study identified a homogeneously enhancing intradural mass at the L2-L3 level. A laminoplasty was performed, followed by tumor resection; no adjuvant treatment was administered afterwards. Immunohistochemical workup confirmed the diagnosis of Ewing's sarcoma in both cases.

Differentiation, proliferation and apoptosis in primary and recurrent primitive neuroectodermal tumors of childhood.

Primitive neuroectodermal tumors (PNETs) of the CNS are a group of embryonal tumors composed of small undifferentiated or poorly differentiated cells. Infratentorially located PNETs are a synonym for medulloblastomas. In this study 31 PNETs, including 5 recurrent tumors, were examined. All children underwent neurosurgery and chemotherapy according to the HIT and HIT-SKK protocols. The specimens were investigated both for their expression of nine immunohistochemical markers for neuronal, astrocytic, mesenchymal and epithelial differentiation and for their proliferation. Results regarding cellular differentiation were confirmed ultrastructurally. Apoptosis was detected by labeling the 3'OH ends generated by DNA fragmentation and by electron microscopy. Glial differentiation was shown to have a prognostic relevance, with an elevated (twofold) risk of recurrence. Neuronal differentiation also indicated a tendency to poor prognosis. Those tumors that recurred later showed an increased proliferation rate (69%) compared with nonrecurrent tumors (58%). Apoptosis was identified in all tumors examined. The proportion of apoptotic cells could not be related to the effect of therapy. These results indicate that cellular differentiation may be a useful predicative factor for the prognosis of cerebral PNETs.

Alternative EWS‐FLI1 fusion gene and MIC2 expression in peripheral and central primitive neuroectodermal tumors

Primitive neuroectodermal tumors (PNET) occur either in the central nervous system (CNS; central PNET, cPNET) or in the peripheral sites (peripheral PNET, pPNET). Recent molecular approaches have been defining a new concept of PNET, that is, the pPNET including Ewing's sarcoma (ES) which expresses MIC2 glycoprotein and shows the specific chimeric gene of EWS‐FLI1. The expression of MIC2 and the genetic rearrangement of EWS‐FLI1 are considered to be highly specific to the pPNET/ES. This study examined the expression of MIC2 and EWS‐FLI1 gene by means of immunohistochemistry and reverse transcriptase–polymerase chain reaction (RT‐PCR) on various small round cell tumors originating in the CNS or non‐CNS organs. All peripheral PNET tested expressed MIC2 and were positive for EWS‐FLI1 (11/11). In contrast, all cPNET and other blastic CNS tumors were negative for MIC2: medulloblastoma (0/3), cerebral PNET (0/2), spinal PNET (0/2), glioblastoma (0/2), retinoblastoma (0/3), and pineoblastoma (0/2). These MIC2‐negative tumors were also negative for the chimeric gene product of EWS‐FLI1. Interestingly, one PNET originating in the intracranial dura mater was positive for both MIC2 and EWS‐FLI1 fusion gene. The results indicate that cPNET lacks any genetic or protein markers, except for a meningeal PNET which falls into the same phenotypic spectrum of pPNET.

Alternative EWS-FLI1 fusion gene and MIC2 expression in peripheral and central primitive neuroectodermal tumors.

Primitive neuroectodermal tumors (PNET) occur either in the central nervous system (CNS; central PNET, cPNET) or in the peripheral sites (peripheral PNET, pPNET). Recent molecular approaches have been defining a new concept of PNET, that is, the pPNET including Ewing's sarcoma (ES) which expresses MIC2 glycoprotein and shows the specific chimeric gene of EWS-FLI1. The expression of MIC2 and the genetic rearrangement of EWS-FLI1 are considered to be highly specific to the pPNET/ES. This study examined the expression of MIC2 and EWS-FLI1 gene by means of immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR) on various small round cell tumors originating in the CNS or non-CNS organs. All peripheral PNET tested expressed MIC2 and were positive for EWS-FLI1 (11/11). In contrast, all cPNET and other blastic CNS tumors were negative for MIC2: medulloblastoma (0/3), cerebral PNET (0/2), spinal PNET (0/2), glioblastoma (0/2), retinoblastoma (0/3), and pineoblastoma (0/2). These MIC2-negative tumors were also negative for the chimeric gene product of EWS-FLI1. Interestingly, one PNET originating in the intracranial dura mater was positive for both MIC2 and EWS-FLI1 fusion gene. The results indicate that cPNET lacks any genetic or protein markers, except for a meningeal PNET which falls into the same phenotypic spectrum of pPNET.

Targeted Oncogenesis Reveals a Distinct Tissue-specific Utilization of Alternative Promoters of the Human Mineralocorticoid Receptor Gene in Transgenic Mice

The human mineralocorticoid receptor (hMR) is a nuclear receptor mediating aldosterone action, whose expression is driven by two alternative promoters, P1 and P2, flanking the two first 5'-untranslated exons. In vivo characterization of hMR regulatory regions was performed by targeted oncogenesis in mice using P1 or P2 directing expression of the large T antigen of SV40 (TAg). While transgenic P1.TAg founders rapidly developed lethal hibernomas from brown fat, cerebral primitive neuroectodermal tumors and facial leiomyosarcomas occurred in P2.TAg mice. Quantitative analyses of mouse MR (mMR) and transgene expression indicate that P1 promoter was transcriptionally active in all MR-expressing tissues, directing strong TAg expression in testis and salivary glands, moderate in lung, brain, uterus, liver, and heart but, unlike mMR, rather low in colon and kidney. Importantly, the renal transgene expression colocalized with mMR in the distal nephron. In contrast, P2 promoter was approximately 10 times less potent than P1, with no activity in the brain and colon. Several immortalized cell lines were established from both neoplastic and normal tissues of transgenic mice. These cells exhibited differentiated characteristics and maintained MR expression, thus providing useful models for further studies exploring the widespread expression and functions of MR. Our results demonstrate that hMR gene expression in vivo is controlled by complex regulatory mechanisms involving distinct tissue-specific utilization of alternative promoters.

Centrosome amplification as a possible mechanism for numerical chromosome aberrations in cerebral primitive neuroectodermal tumors with TP53 mutations

Although alterations in chromosome number have frequently been detected in human tumor cells and associated with tumor initiation and progression, the causal mechanisms are still not understood. One protein known to be involved in maintaining genetic stability is tumor suppressor p53. In mice, p53 has been implicated in the maintenance of diploidy (Cross et al., 1995) and the regulation of centrosome duplication (Fukasawa et al., 1996). Here we report on cerebral primitive neuroectodermal tumors that lacked the wild-type p53 gene (TP53) and showed multiple numerical chromosome aberrations, as detected by comparative genomic hybridization. In these tumors, the centrosome number was significantly higher than in a control tumor without a detected TP53 mutation and with few chromosomal imbalances. These findings indicate that abnormal centrosome amplification can occur in human tumors lacking wild-type TP53 and may be a mechanism by which numerical chromosome aberrations are generated.

MYCN Amplification in Pediatric Brain Tumors: Detection by Differential Polymerase Chain Reaction

MYCN amplification is frequently observed in tumors such as neuroblastomas, but is uncommon in pediatric brain tumors, which represent the most common solid tumors of childhood. MYCN amplification is rarely described in gliomas and some primitive neuroectodermal tumors (PNETs) of the central nervous system. Oncogene amplification has traditionally been determined quantitatively by Southern blotting, a time consuming technique often requiring more DNA than is available from small brain tumor biopsies. We applied the novel technique of differential polymerase chain reaction (PCR) to a small series of 8 pediatric brain tumors to assess the presence of MYCN amplification. The tumors included 4 cerebellar PNETs, 1 cerebral PNET, 1 malignant glioma, 1 subependymal giant cell tumor, and 1 ganglioglioma. Differential PCR showed MYCN amplification in 1 cerebellar PNET and 1 malignant glioma, with amplification 20-fold and 80-fold, respectively, above diploid controls. Our results confirm that differential PCR is a useful technique to assess oncogene amplification in pediatric brain tumors. (The J Histotechnol 20:115, 1997)

P53 gene mutation in cerebral primitive neuroectodermal tumor in Taiwan.

p53 mutation has been rarely reported in cerebral primitive neuroectodermal tumors (PNET). To determine the significance of p53 mutations in the development of cerebral PNET, we studied cerebral PNET samples from 14 patients, 8 females and 6 males with a mean age of 38 years (range 10 months to 77 years) who had total or subtotal surgical resection. Histological typing of PNET with neuronal (N) and non-neuronal (NN) differentiation groups revealed 8 and 6 cases, respectively. Six (43%) of the 14 patients had p53 mutation. The p53(+) and p53(-) groups had an age range of 19-77 with a mean of 49 years and 10 months to 57 years with a mean of 30 years, respectively. p53 expression between the PNET-N and PNET-NN groups was 5 of 8 (62.5%) and 1 of 6 (16.7%), respectively. The mutations contained 3 transitions, 2 transversions and 1 frameshift; none of them occurred at the site of 'hot-spot' residues (codons 175, 248, 273). The results suggest that: (1) p53 mutation in cerebral PNET tends to show a higher incidence of neuronal differentiation and occurs in the older age group in Taiwan, (2) there was no difference in survival time between the PNET-N and PNET-NN groups (7 months and 6 months) (P = 0.54), and between p53(+) and p53(-) groups (6 months and 7 months) (P = 0.57), and (3) PNET may be an entity of a heterogenous group of tumors with different genetic mechanisms controlling their trends of differential lineage. Further studies are needed to determine the significance of p53 mutations in PNET development, especially the role of carcinogens in the genesis of PNET in Taiwan.

Cerebral primitive neuroectodermal tumors in childhood.

A series of 17 infants and children with cerebral primitive neuroectodermal tumors (PNETs) detected by computed tomography is presented. The pertinent literature is reviewed. Because of ongoing nosological difficulty, we include in this series only those tumors which are located in the cerebral hemisphere, and are composed of predominantly undifferentiated neuroepithelial tumor with or without glial or neuronal differentiation. The prognosis of the patients with cerebral PNETs remains poor despite treatment including surgical resection, radiation therapy and/or chemotherapy. Only two patients had a long term survival more than 4 years in this series. The histological features and the extent of surgical resection did not influence the patients survival. Nevertheless, visible total resection afforded better control of local disease of the primary site, but remote metastases along the cerebrospinal fluid pathway were frequent at relapse. The patients with cerebral PNETs appear to be best treated with radical gross total resection, postoperative radiation therapy including irradiation to the neuraxis and aggressive chemotherapy.

PCNU and recurrent childhood brain tumors.

PCNU, the latest nitrosourea analogue to be subjected to clinical trials, held promise as a superior chemotherapy agent for brain tumors because of more favorable biochemical and cytotoxic characteristics in laboratory studies. Thirty-nine children with a variety of recurrent primary CNS tumors, all of whom had evaluable disease, participated in a phase II PCNU trial. Their mean age was 9.7 (3-20) years. PCNU was administered as a 2 hour intravenous infusion in one of 2 dose schedules at 6-7 week intervals; 100-125 mg/m2 for minimally treated patients and 70-90 mg/m2 for heavily treated patients. Response was assessed after 2 courses of chemotherapy after attempting to taper the steroid dose. The overall objective response rate was 18% (7/39) for a mean of 5.9 months (2+ -12). Only partial responses were observed. Disease-specific responses rates were: brainstem glioma--18% (3/17); cerebral glioma--27% (3/12); ependymoma--1/1; and primitive neuroectodermal tumors--(0/9) including 5 medulloblastomas, 2 pineoblastomas and 3 cerebral primitive neuroectodermal tumors. Toxicity was primarily hematologic and clinically significant thrombocytopenia (less than 50,000 mm3) was encountered in 30/38 (79%) patient trials. Modest activity of PCNU in recurrent childhood gliomas is confirmed. Our response rates, using objective CT criteria, are somewhat lower than those reported for BCNU and CCNU. Because of comparable hematologic toxicity and efficacy, intravenous PCNU does not appear to offer a clinical advantage to existing nitrosoureas for children with recurrent brain tumors using a 2 hour intravenous infusion schedule.