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PubMed1995

Gamma knife radiosurgery for malignant tumors.

Between May 1990, and June 1994, 79 patients with malignant tumors were treated radiosurgically using a Leksell gamma unit at Asan Medical Center. Of these patients, 57 were metastatic brain tumor, 12 were glioblastoma multiforme (GM), 4 were primitive neuroectodermal tumor, 3 were malignant germ cell tumor, 2 were recurrent lymphoma, and 1 was adenoid cystic carcinoma of the orbit. Among 57 patients with metastatic tumors, 28 patients harboring 60 tumors were followed clinically and radiographically. The median marginal dose for these tumors was 30 Gy and the median survival rate was 15 months. Twenty-one tumors disappeared and 32 tumors decreased in size during 2 to 6 months after radiosurgery on computed tomographic or magnetic resonance imaging scans. All 12 patients with GM were treated with conventional radiation (6,240 approximately 6,500 cGy) after surgical resection or biopsy prior to radiosurgery (13 approximately 15 Gy to margin). The results were varied. Radiosurgical treatment of two recurrent lymphomas and three recurrent mixed germ cell tumors after radiation and chemotherapy provided rapid clinical improvement with disappearance of the tumor. However, new lesions appeared in two lymphomas and one mixed germ cell tumor within 3 to 4 months. One patient with adenoid cystic carcinoma of the orbit, who was treated radiosurgically prior to resection, is alive without recurrence 31 months after the treatment. Gamma knife radiosurgery appears to be the best alternative method to surgical excision plus radiation therapy for single and multiple cerebral metastases. It also provides rapid palliation of symptoms due to recurrent malignant tumors. And it may have an adjuvant role in the treatment of some tumors delaying local recurrence, if given prior to resection. However, the preliminary results for the malignant gliomas were inconclusive.

Adult↗
PubMed1992

Diagnostic histopathology, cytogenetics, and molecular markers of pediatric brain tumors.

The purpose of this article is to summarize some of the current issues in diagnostic histopathology and to provide an update of both molecular and cytogenetic studies of the most commonly encountered pediatric brain tumors. Most of the discussion focuses on astrocytomas, primitive neuroectodermal tumors and medulloblastomas, and ependymomas because they make up the majority of these neoplasms. A few comments on choroid plexus tumors are also included.

Astrocytoma↗
PubMedDate not supplied

Primary meningeal tumors in children: correlation of clinical and CT findings with histologic type and prognosis.

PURPOSE: To identify the radiologic features that might help in preoperative differentiation of the meningiomas from the remaining primary meningeal tumors, in particular the malignant tumors. METHODS: The clinical and computed tomographic features of 21 children with histologically proved primary meningeal tumors were analyzed. FINDINGS: Benign tumors (meningiomas) are more likely to occur in older children, to have longer symptom duration, and to have CT appearances similar to the "typical" adult meningioma. Atypical CT features suggest a malignant meningeal tumor, such as meningeal sarcoma, melanoma, or meningeal primitive neuroectodermal tumor. The recent identification of a new subtype of meningioma (a "sclerosing" group) is discussed. This is common in children and the CT and clinical features are similar to those seen in other meningiomas. It is frequently mistaken histologically for an intraaxial tumor, or for an atypical or malignant meningioma. These sclerosing meningiomas may also show brain invasion but despite this, in the short term, the prognosis is no different from other meningiomas. CONCLUSION: The bad reputation previously ascribed to childhood primary meningeal tumors should be confined to that small group that are malignant. Meningiomas have a more favorable outlook.

Adolescent↗
PubMed1992

Flow and image cytometric DNA analysis in Ewing's sarcoma.

Ewing's sarcoma is the second most common bone tumor in childhood, with an overall 5-yr survival of 40%. It is one of the poorly differentiated small spherical cell tumors frequently requiring distinction from rhabdomyosarcoma, neuroblastoma, osteosarcoma, primitive neuroectodermal tumor, and lymphoma. The majority of rhabdomyosarcomas, neuroblastomas, and osteosarcomas are aneuploid, whereas Ewing's sarcomas are usually diploid. To determine whether there is any correlation between DNA content, morphology, site, and survival in Ewing's sarcoma and extraosseous Ewing's sarcoma, 21 tumor samples were studied retrospectively (3 extraosseous Ewing's and 18 Ewing's sarcomas). The DNA analysis was performed on disaggregated paraffin-embedded tissue nuclei by flow (FCM) and image (IC) cytometry and correlated with the histology and clinical history. The DNA ploidy by FCM on 17 of 18 Ewing's sarcoma samples was 12 diploid, 1 aneuploid, and 4 tetraploid. By IC, the DNA ploidy on 16 samples was 13 diploid, 1 aneuploid, and 2 tetraploid. Three samples were nonevaluable (1 by FCM and 2 by IC). The agreement between FCM and IC was 12 of 16 (75%). The extraosseous Ewing's sarcoma tumors were 2 diploid and 1 aneuploid by IC. In this study there was no correlation between the DNA ploidy and either the histology, site, or survival.

Adolescent↗
PubMed1990

The neuroendocrine and neural profiles of neuroblastomas, ganglioneuroblastomas, and ganglioneuromas.

To establish the neuroendocrine and neural features of peripheral neuroblastic tumors, a prospectively collected group of 12 neuroblastomas (NB), 2 ganglioneuroblastomas (GNB), and 4 ganglioneuromas (GN) was probed with a panel of monoclonal antibodies (MAbs) to neuroendocrine and neural antigens. All tumors expressed the pan-neuroendocrine markers synaptophysin and chromogranin A. They also showed extensive expression of neuronal antigens, ie, of each of the neurofilament (NF) triplet proteins and of the microtubule-associated proteins (MAPs) MAP2 and tau-protein. However, only in the GNBs and GNs was the pattern of NF phosphoisoforms relatively mature. In the latter tumors glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP) could be demonstrated as well, suggesting the presence of nonmyelinating and myelinating Schwann cells, respectively. The glial markers did not colocalize with the neural markers. On the basis of these data, it was concluded that all peripheral neuroblastic tumors manifest molecular characteristics of neuroendocrine cells and of neurons. The latter were most developed in GNBs and GNs, in which they were accompanied by Schwann cell differentiation in a separate population of cells. The above-outlined neuronal profile of peripheral neuroblastic tumors, including NBs, distinguishes this group of tumors from the much-less neuronally differentiated primitive neuroectodermal tumors of the central nervous system.

Abdominal Neoplasms↗
PubMed1999

High-dose chemotherapy with autologous hematopoietic stem-cell rescue for patients with malignant brain tumors.

This article reviews recent reports on high-dose chemotherapy combined with autologous stem-cell rescue for patients with newly diagnosed or recurrent malignant brain tumors. Children with newly diagnosed malignant central nervous system (CNS) tumors are included - in these patients it was desirable to avoid radiotherapy. The drugs used were thiotepa, etoposide, cyclophosphamide, busulfan, melphalan, and carboplatin. At a toxic death rate of 8-13%, their toxicity was considered acceptable. However, in patients receiving high-dose chemotherapy, neurologic complications were not uncommon. Therefore, the effects of this drug therapy on the post-treatment cognitive function of long-term survivors must be examined prospectively. Regarding the types of tumor that respond to drug therapy, medulloblastoma and cerebral primitive neuroectodermal tumor (PNET) appear to be good candidates, as are malignant astrocytic tumors in the cerebral hemisphere of children younger than 3 years. On the other hand, brain stem gliomas do not appear to respond well to high-dose chemotherapy. Radiotherapy can be avoided in a significant proportion of young children with malignant brain tumors. Larger patient series need to be studied to determine which patients are most likely to benefit from high-dose chemotherapy and to pinpoint the optimal time for treatment intervention.

Journal Article↗
PubMed1994

Congenital "neurovascular hamartoma" of the skin. A possible marker of malignant rhabdoid tumor.

Distinct congenital, benign, probably hamartomatous, lesions of the upper dermis were noted in two children who subsequently developed malignant rhabdoid tumors. The dermal lesions, which we have named "neurovascular hamartomas" were characterized by a proliferation of capillaries in a background of bland spindle cells with possible neural features. In one child the malignant rhabdoid tumor was located in the kidney, and a synchronous primitive neuroectodermal tumor of the central nervous system was the cause of his death. The other infant had two neurovascular hamartomas, and a malignant rhabdoid tumor arose in contiguity with the deepest portion of the larger of the two hamartomas. An axillary lymph node metastasis rapidly developed in this child followed by widespread metastases and death 3 months later. Neuroectodermal differentiation was observed immunohistochemically or ultrastructurally in all rhabdoid tumors and in the tumor of the brain. This is the first report of a unique congenital benign dermal lesion that appears to be associated with malignant rhabdoid tumors in very young children. A genetic abnormality of neuroectodermal differentiation may underlie the development of these neoplasms.

Hemangioma↗
PubMed1997

High-dose chemotherapy with autologous stem-cell rescue in patients with recurrent and high-risk pediatric brain tumors.

PURPOSE: We treated 49 patients with recurrent or poor-prognosis CNS malignancies with high-dose chemotherapy regimens followed by autologous marrow rescue with or without peripheral-blood stem-cell augmentation to determine the toxicity of and event-free survival after these regimens. PATIENTS AND METHODS: Nineteen patients had medulloblastomas, 12 had glial tumors, seven had pineoblastomas, five had ependymomas, three had primitive neuroectodermal tumors, two had germ cell tumors, and one had fibrosarcoma. Thirty-seven received chemotherapy with cyclophosphamide 1.5 g/m2 daily x 4 and melphalan 25 to 60 mg/m2 daily x 3. Nine received busulfan 37.5 mg/m2 every 6 hours x 16 and melphalan 180 mg/m2 (n = 7) or 140 mg/m2 (n = 2). Three received carboplatin 700 mg/m2/d on days -7, -5, and -3 and etoposide 500 mg/m2/d on days -6, -4, and -2. All patients received standard supportive care. RESULTS: Eighteen of 49 patients survive event-free 22+ to 55+ months (median, 33+) after transplantation, including nine of 16 treated before recurrence and nine of 33 treated after recurrence. There was one transplant-related death from pulmonary aspergillosis. Of five patients assessable for disease response, one had a partial remission (2 months), one has had stable disease (55+ months), and three showed progression 2, 5, and 8 months after transplantation. CONCLUSION: The toxicity of these regimens was tolerable. Certain patients with high-risk CNS malignancies may benefit from such a treatment approach. Subsequent trials should attempt to determine which patients are most likely to benefit from high-dose chemotherapy with autologous stem-cell rescue.

Adolescent↗
PubMed1995

The applicability of Collins' Law to childhood brain tumors and its usefulness as a predictor of survival.

In 1955, Collins made the observation that tumor recurrence in children with Wilms' tumor was correlated with the child's age plus 9 months. This concept of a period of risk for recurrence was later applied to a variety of tumors in children and became known as Collins' Law (CL). The law has been a successful predictor of survival for some children with neural tumors within the central nervous system and a poor predictor for others. We tested Collins' concept of a period of risk for recurrence and extended it to survival for 14 childhood neural tumors described in the Childhood Brain Tumor Consortium (CBTC) database. The CBTC data describe clinical, surgical, and histological details (over a 49-year period in 10 institutions) from 3921 patients under the age of 21 years at the time of their first surgical procedure for a brain tumor. CL was considered to be a good predictor of survival if fewer than 10% of patients who die survive beyond the expiration of the period of risk for that child. We found that CL applied to tumors such as anaplastic astrocytoma, glioblastoma, pineoblastoma, medulloblastoma or "primitive neuroectodermal tumor," teratoma, and germinoma, as well as ependymoma, papilloma, and tumors that could not be classified; it had no predictive value in craniopharyngioma, oligodendroglioma, or plain, fibrillary, pilocytic, or protoplasmic astrocytoma. We had sufficient follow-up data to determine adherence to CL when the child's age at diagnosis was less than 8 years; it is likely that CL applies to older children with these tumors, but we did not have the data to show this unequivocally.

Adolescent↗
PubMedDate not supplied

Primary bone tumors and pseudotumors of the lumbosacral spine.

Primary tumors of the spine are relatively infrequent lesions compared with metastatic disease, multiple myeloma, and lymphoma which are the more frequent neoplasms of the spine and usually manifest with multifocal lesions and thus pose little diagnostic dilemma. However, in the presence of a solitary spinal lesion, the more uncommon primary tumors of the spine represent an important group of entities for diagnostic consideration. The most common benign and malignant primary tumors of the spine are enostosis, osteoid osteoma, osteoblastoma, giant cell tumor, aneurysmal bone cyst, osteochondroma, chordoma, chondrosarcoma, Ewing sarcoma, primitive neuroectodermal tumor, and osteosarcoma. The imaging features of these lesions are often characteristic. Radiologists should be aware of the appearance of these unusual tumors in order to provide a complete differential diagnosis.

Diagnosis, Differential↗
PubMed1992

Synaptophysin expression in "ependymal tumors" induced by ethyl-nitrosourea in rats.

Synaptophysin expression was studied in seven "ependymomas" induced by transplacental administration of ethyl-nitrosourea in rats. In all the cases, strong positivity for synaptophysin was found on tumor cells. This finding supports previous studies suggesting that ENU-induced brain tumors considered to be ependymal neoplasms, are, in fact, primitive neuroectodermal tumors.

Animals↗
PubMed1991

Clues and pitfalls in stereotactic biopsy of the central nervous system.

We present a 6-year experience on 307 stereotactic biopsy specimens of the central nervous system using Leksell's and Talairach's systems independently and either Leksell or Sedan needles. Patients with deep cerebral lesions (basal ganglia, parasellar, pineal, or third ventricle), those located in highly functional areas or those poorly defined on imaging studies, as well as candidates for brachytherapy, were selected. Smear examination during surgery was a routine procedure followed by conventional histologic methods. Ages ranged from 8 months to 81 years (mean, 33.64 years). The series comprised 258 tumors, 28 nonneoplastic cases, and 21 nondiagnostic samples. Of the 258 tumors, 179 were supratentorial, 28 were infratentorial, 36 were of the pineal area, and 15 were from sellar and suprasellar regions. Results of the histologic examination showed the following: astrocytic tumors, 148 (57.36%); oligodendroglial, 25 (9.68%); ependymal, six (2.32%); primitive neuroectodermal tumors, 17, including 14 pineoblastomas (5.45%) and three medulloblastomas (1.16%), seven lymphomas (2.71%), seven meningiomas (2.71%), four schwannomas (1.55%), eight craniopharyngiomas (3.10%), 12 germinomas (4.65%), and 20 metastases (7.78%). Nontumoral cases included six arteriovenous malformations, six pyogenic lesions, seven infarcts, two hematomas, one multiple sclerosis plaque, one Fahr, one progressive multifocal leukoencephalopathy, one tuberculosis, one cysticercosis, and one Chagas' encephalitis. Awareness of the cerebellar granular layer in infratentorial targets as well as glial reaction around craniopharyngiomas is essential to avoid misdiagnosis. Difficulties were basically differential diagnosis between well-differentiated astrocytomas vs glial reaction, as well as poorly differentiated neoplasms vs metastases.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1990

Myogenic regulatory protein (MyoD1) expression in childhood solid tumors: diagnostic utility in rhabdomyosarcoma.

Transcripts for the muscle regulatory gene MyoD1 are expressed during normal skeletal muscle myogenesis and in rhabdomyosarcomas but not in other tissues or in soft-tissue sarcomas. Here we report the distribution of MyoD1 protein, determined by reactivity with anti-MyoD1 polyclonal sera in normal tissues, rhabdomyosarcoma cell lines, and in a variety of pediatric solid tumors. The distribution of MyoD1 protein was highly restricted in normal tissues and was detected only in fetal skeletal muscle and more faintly in adult skeletal muscle. All six human rhabdomyosarcoma cell lines analyzed expressed MyoD1 mRNA transcripts as well as immunoreactive protein. The immunohistochemical expression of MyoD1 protein was then examined in 49 surgical specimens from a variety of pediatric solid tumors. Each of 16 rhabdomyosarcoma specimens was positive for MyoD1, including four that did not express the intermediate filament protein desmin. Two of five specimens originally designated sarcoma type indeterminate (STI) and two of three specimens originally designated extraosseous Ewing's sarcoma (EOE) were positive for MyoD1, suggesting commitment to myogenic differentiation. Three of eight Wilms' tumors, which also expressed desmin and had clearly evident myogenic elements, also were positive for MyoD1. Tumors that failed to express MyoD1 protein included neuroblastoma, primitive neuroectodermal tumor, non-Hodgkins lymphoma, embryonal sarcoma of the liver, malignant fibrous histiocytoma, malignant rhabdoid tumor, and Ewing's sarcoma of the bone. These results indicate that expression of MyoD1 protein is highly restricted in normal human tissues and that expression of this gene product in malignant tissue may be diagnostic for rhabdomyosarcoma. Furthermore MyoD1 staining may be a valuable adjunct in the classification of pediatric soft-tissue sarcomas.

Child↗
PubMed1993

Expression of transforming growth factor-beta isoforms in small round cell tumors of childhood. An immunohistochemical study.

The transforming growth factor (TGF)-betas are a highly conserved group of potent multifunctional cell regulatory proteins with variable effects on cell growth and differentiation. Most of the small round cell group of childhood tumors are thought to arise from either primitive mesenchyme or neuroectoderm and show evidence of skeletal muscle or neural differentiation, and rarely both. To investigate the possibility that the TGF-betas have a role in the growth or differentiation of these neoplasms, we used antibodies specific for peptide sequences of the three known mammalian TGF-beta isoforms (TGF-betas 1, 2, and 3) to probe for TGF-beta protein expression in a total of 49 cases. TGF-beta 1 immunoreactivity was present in 16/17 (94%) of rhabdomyosarcomas, and the staining intensity was usually strong. TGF-beta 1 was also present in three of three ectomesenchymomas. In contrast, TGF-beta 1 was absent in all but one out of nine poorly differentiated neuroblastomas. Differentiating neuronal cells of ganglioneuroblastomas, however, were strongly positive for TGF-beta 1. Ewing's sarcomas and peripheral primitive neuroectodermal tumors had a less consistent, but usually positive, staining pattern. TGF-beta 3 staining patterns were very similar to those of TGF-beta 1. TGF-beta 2 immunoreactivity was only rarely detected in this group of tumors. The results suggest different roles for TGF-betas 1 and 3 in neuroblastoma and rhabdomyosarcoma. Expression of TGF-betas 1 and 3 is associated with neuronal differentiation of neuroblastoma. In contrast, these proteins may promote the growth of rhabdomyosarcoma by suppressing differentiation.

Adolescent↗
PubMed1998

Induction of brain tumors in mice using a recombinant platelet-derived growth factor B-chain retrovirus.

In existing mouse models for malignant brain tumors, genes with no proven pathogenical relevance for humans have been used. Coexpression of platelet-derived growth factor (PDGF) and PDGF receptors suggests an autocrine mechanism of growth factor stimulation in the development of brain tumors in man. A murine retrovirus coding for the PDGF B-chain was, therefore, used to induce brain tumors in mice. Of 35 mice who received injections, 15 developed brain tumors of oligo- or monoclonal origin. They coexpressed PDGF B-chain and alpha-receptor mRNA, as expected, from an autocrine mechanism of transformation. Most tumors displayed characteristics of glioblastoma multiforme or of a primitive neuroectodermal tumor, and the consistent expression of nestin suggested that they were all derived from an immature neuroglial progenitor. The results show that an autocrine mechanism of transformation may be an initial or early event in neuro-oncogenesis. The present model provides an ideal system for studies of genetic mechanisms involved in the development of brain tumors.

3T3 Cells↗
PubMed1989

Immunocytochemical and ultrastructural studies of the histogenesis of Ewing's sarcoma and putatively related tumors.

The histogenesis of Ewing's sarcoma (EW) and extraskeletal Ewing's sarcoma (EEW) is still disputable. Their relationship to the so-called Askin's tumor, neuroectodermal tumor of bone, and peripheral neuroblastoma remains to be established. In an attempt to clarify these points, immunocytochemical and ultrastructural studies were done on tissues from 14 cases of EW, 4 cases of EEW, and 9 cases of primitive neuroectodermal tumor (PNET) and compared with neuroblastoma and olfactory neuroblastoma. Six tumors categorized initially as EW and EEW on biopsy, turned out to be PNET by extensive histologic and/or ultrastructural observations. Abundant glycogen was recognized not only in 16 of 18 cases of EW and EEW, but also in seven of nine cases of PNET. Fine fibrillar cell processes were seen between tumor cells, at least in limited areas even in cases of EW and EEW. Immunocytochemically, neuron-specific enolase (NSE), neuroblastoma cell surface antigen (NBCA), neuron cell surface antigen (NCSA), and neurofilament (NF) were demonstrated not only in neuroblastoma, but also frequently in cases of EW, EEW, and PNET. The results seem to suggest that EW and EEW represent the most immature forms of neuroectodermal tumor. Electron microscopic study showed predominantly primitive cells with occasional areas of cell processes, neurosecretory granules, and microtubules, suggesting a neuroectodermal origin.

Adolescent↗
PubMed2006

Temozolomide in resistant or relapsed pediatric solid tumors.

PURPOSE: We report the off-label study aimed at investigating the use of temozolomide (TMZ) as single agent in relapsed or resistant pediatric solid tumors. The drug was administered at the dose of 215 mg/m2/day x 5 days or 180 mg/m2/day x 5 days in patients with prior craniospinal irradiation (CSI) or autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS: Fifty two patients, median age 127.6 months, with resistant or relapsed solid tumors were enrolled. Tumor types were: neuroblastoma (NB; n = 17), medulloblastoma (MB; 8), brain stem glioma (BSG; 8), extraosseous Ewing's sarcoma/peripheral neuroectodermal tumor (EOES; 4), Ewing's sarcoma (ES; 4), anaplastic astrocytoma (AA; 3), rhabdomyosarcoma (RMS; 2), ependymoma (EP; 2), cerebral primitive neuroectodermal tumor (cPNET; 2), hepatocarcinoma (HC; 1), and osteosarcoma (OS; 1). All patients were pre-treated. Two outpatient courses were administered, with a median of 4.8 courses/pt. RESULTS: Objective response-rate (CR + PR + MR) in our series was 13.4% (1.9% CR, 3.8% PR, and 7.7% MR), SD occurred in 38.4% of patients and 48% had PD. The median survival was 7.8 months (range 1-37) and median time to progression was 3.4 months (range 1-20); these data were significantly correlated with histology and previous nitrosureas administration in multivariate analysis. Haematological toxicity grade 3-4 (mainly thrombocytopenia) was observed in 21.4% of administered courses, nausea was reported in 3.1% and respiratory distress in 0.7%. CONCLUSION: Oral TMZ was well tolerated in children with resistant or relapsed solid tumors and showed activity in NB and CNS tumours refractory to standard chemotherapy.

Adolescent↗
PubMed2003

Induction of tenascin-C by tumor-specific EWS-ETS fusion genes.

Ewing sarcoma (ES) and peripheral primitive neuroectodermal tumors (PNETs) are associated with a chromosomal translocation resulting in a fusion of the amino-terminus of EWS with the DNA-binding domain of an ETS transcription factor (most commonly FLI1 or ERG). Although previous reports suggested that these chimera proteins would act as aberrant transcription factors, their downstream targets have not been fully elucidated. To identify downstream targets of these EWS-ETS fusion proteins, we introduced EWS-ETS fusion constructs into a human fibrosarcoma cell line, HT-1080, by retroviral transduction. Here we report that Tenascin-C (TNC) is induced to a significantly higher level in cells expressing EWS-ETSs than in cells expressing normal ETSs. Furthermore, through use of an antisense cDNA expression vector we show that expression of endogenous TNC mRNA and protein were reduced coordinately with attenuation of EWS-FLI1 fusion protein expression. A chromatin immunoprecipitation assay showed direct interaction between the TNC promoter and the EWS-FLI1 fusion protein in vivo. In addition, a luciferase reporter assay revealed that EWS-ETSs upregulated the TNC gene through four ETS binding sites in the TNC promoter. High levels of TNC expression were observed in a subset of ES cell lines (3 of 6) and primary tumors (4 of 6). Together with previous studies showing that TNC expression is involved in the invasive and malignant phenotype of several tumor types, our data suggest that the oncogenic effect of EWS-ETS may be mediated in part by upregulating of TNC expression.

DNA, Antisense↗