Features Of Neuroblastoma Research Articles

Neuroblastoma in Southern Brazil

The authors report on the incidence and clinical characteristics of neuroblastoma in southern Brazil. The aims of the study were to evaluate the age at diagnosis, tumor stage, MYCN status, and tumor histopathology, and to relate these factors to survival. All patients with neuroblastoma, 15 years old or younger (n = 125), admitted to the three major pediatric oncology hospitals in the state of Parana over a period of 11 years (between January 1990 and December 2000), were included in the analysis. All patients were followed for at least 5 years. In addition, a FISH evaluation for MYCN status was conducted in a subset of 34 tumors. Overall survival for tumor stages 1, 2, 3, and 4 was 100%, 72%, 59%, and 17%, respectively. Sixty-two percent (77/125) of all patients were older than 2 years; these represented 71% (57/80) of the patients with stage 4 disease. Children who presented with an unfavorable histopathology had a significantly worse prognosis (20% survival) than children with a favorable histopathology (67% survival). MYCN amplification was detected most commonly in stages 3 and 4 tumors (13/16). These data showed a delayed diagnosis of neuroblastoma in children in southern Brazil, and consequently survival was considerably lower in these patients.

High expression of the novel endothelin-converting enzyme genes, Nbla03145/ECEL1α and β, is associated with favorable prognosis in human neuroblastomas

The clinicobiological feature of neuroblastoma is enigmatic because spontaneous regression often occurs in early stages of tumors of the patients under 1 year of age, while rapid growth usually occurs in the tumors of the patients over 1 year of age. Such difference in the clinical behavior may be caused by the difference in the pattern of gene expression among the subsets of neuroblastoma. To understand the molecular basis of neuroblastoma biology, we decided to identify the novel genes expressed differentially between favorable and unfavorable neuroblastomas. The oligo-capping cDNA libraries were constructed from different subsets of neuroblastomas. After random selection and DNA sequencing, the differentially expressed genes between favorable and unfavorable neuroblastomas were screened by reverse transcriptase-PCR. The clinical significance of gene expression was evaluated based on the results of Northern blot analysis. We have identified a novel gene Nbla03145 (alpha), also cloned and termed by another group as ECEL1, which encodes a new member of putative zinc-binding metalloendopeptidase (endothelin-converting enzyme) with unknown substrate. We also cloned a COOH-terminally truncated Nbla03145/ECEL1beta which is expressed only in thymus. In primary NBLs, the alpha isoform is more preferentially expressed than the beta isoform. High levels of Nbla03145/ECEL1 expression were significantly correlated with a younger age (p=0.0005), lower stages (p=0.0019), high level of TrkA expression (p</=0.00005), a single copy of MYCN (p<0.00005) and the tumors found by mass screening (p<0.00005). Decreased expression of Nbla03145/ECEL1 mRNA was significantly associated with poor prognosis (log-rank test: p=0.012). The present results have shown that expression of Nbla03145/ECEL1 is a novel prognostic marker of neuroblastoma. Further analysis of the gene may also give a cue to the understanding of the role of endothelin-like signaling in neuroblastoma and to the development of diagnostic and therapeutic strategies against aggressive tumors.

Testicular and paratesticular involvement by metastatic neuroblastoma.

Testicular and paratesticular involvement is a less familiar feature in neuroblastoma and its prognostic impact is unclear. The records of 1076 male patients in the German cooperative neuroblastoma treatment trials were searched for patients with testicular or paratesticular involvement. The authors found 11 children with paratesticular or testicular involvement at the time of manifestation of the disease, 3 children with testicular involvement at the time of relapse, and 1 infant with testicular involvement at the time of progression of neuroblastoma from International Neuroblastoma Staging System (INSS) Stage 4S to Stage 4. In de novo disease, the age of manifestation did not exceed 12 months. Two children had paratesticular involvement per continuitatem by growth of a primary tumor through the inguinal channel. All others had distant primary tumor. Prognosis appeared more favorable for infants (3 of 9 died) than for older children (5 of 6 died), for children with involvement of testes and < 10% involvement of bone marrow (2 of 8 died) than for children with other distant metastasis (6 of 7 died), and for children with intrascrotal involvement at first diagnosis (4 of 11 died) than for children with intrascrotal involvement during relapse of the disease (all 4 children died). Paratesticular or testicular metastasis does not per se indicate unfavorable outcome and is compatible with INSS Stage 4S in infants. The age at diagnosis and the time of manifestation during disease contributed to the prognosis in those patients.

Neuroblastoma.

The neuroblastic tumours originate from primordial neural crest cells that normally develop into sympathetic nervous system, including the adrenal medulla. Neuroblastoma is the most intriguing pediatric neoplasm displaying diverse clinical and biologic characteristics and natural history. It has the highest rate of spontaneous regression of all human cancers, yet exhibits extremely malignant behaviour in older children with regional and disseminated disease. In the last 30 years, only a nominal improvement has occurred in the outlook of older children with metastatic disease at diagnosis. Tremendous gains in understanding of the biology of neuroblastoma in recent years have led to development of risk-related therapy based on age, stage and biological characteristics of neuroblastoma.

Current Management of Neuroblastoma

Neuroblastoma is one of the more common pediatric cancers. Although there have undoubtedly been major advances in therapy over recent decades, there is still room for significant improvements in outcome to be made. Neuroblastoma is a disease with a variable outlook, encompassing a spectrum-from patients with disease which may undergo spontaneous regression, through those who may be cured with limited treatment, to others whose disease is refractory even to the most aggressive management strategies. Great progress has been made toward understanding the basic biology of the disease, which allows reliable allocation of individual patients to good, intermediate, or poor prognostic groups and aids selection of appropriate therapeutic approaches. Unfortunately, attempts to improve the outcome of patients with adverse prognostic factors have been less effective. This paper reviews the clinical and biological features of neuroblastoma which determine outcome, and outlines current management policies. Some experimental approaches involving translational research which seek to exploit the unique biology of neuroblastoma are discussed. Although currently unproven, such new treatments are undergoing clinical evaluation and may yet offer new hope for patients with this enigmatic disease.

Screening for neuroblastoma in late infancy by use of EIA (enzyme-linked immunoassay) method: 115 000 screened infants in Austria

The aim of this study was to investigate the feasibility of a neuroblastoma screening programme for children in late infancy, based on collaboration of general paediatricians and practitioners in Austria, using the technique of enzyme-linked immunoassay (EIA) for biochemical analyses. Analysis of catecholamine metabolites in spot urine samples by EIA with high performance liquid chromatography as a backup was undertaken. Austrian infants (median age 8.7 months) were screened. Overall compliance was 30%. The EIA method had a high rate (6.7%) of false-positive results. 28 infants were admitted to hospital. In 15 cases, neuroblastoma was found (four stage 1, five stage 2B, six stage 3). The EIA method can be used for neuroblastoma screening, but requires a backup analytical technique in order to avoid unnecessary hospital admissions. The stage distribution and biological features of neuroblastomas diagnosed by screening at a later age are different from those detected by earlier screening. Screening in late infancy might be of more benefit than early screening.

Ultrasound Differentiation of Two Pediatric Abdominal Masses

Neuroblastoma and Wilms' tumor are the two most common abdominal malignancies encountered in pediatric patients. Neuroblastoma generally arises from the adrenal gland, whereas Wilms' tumors arise from the kidney. Recognition of the clinical symptoms, laboratory values, and sonographic appearances of these two entities can provide valuable information on location and extent of the neoplasm. Early detection of a neoplasm improves the survival rate of patients. The purpose of this article is to review characteristics and features of neuroblastoma and Wilms' tumor that will aid in the differential diagnosis of these tumors.

Neuroblastoma as a prominent component of a mixed germ cell tumor of testis

Primitive neuroectodermal tissue in teratomas of testis has been reported in the literature. A mixed germ cell tumor of testis with a prominent neuroblastoma component dictating the clinical behavior was found to be unique. Tissue sections were stained with hematoxylin and eosin, and immunohistochemical, ultrastructural, cytogenetic, and flow cytometric analyses were performed on the primitive neuroectodermal component of the testicular mass. Follow-up results at 2.5 years are included. The microscopic findings on hematoxylin and eosin slides showed cells composing the majority of the neoplasm to have features of neuroblastoma. The immunohistochemical stains showed positivity for neuron-specific enolase in the cells comprising the neuroblastoma, and transmission electron microscopic study corroborated these findings by demonstrating microtubules and rare membrane-limited, dense-core granules in the cytoplasm. Flow cytometry showed a hypertetraploid population with a large aneuploid DNA content. Cytogenetics revealed a hypertriploid modal number of 74 chromosomes. The clinical features were dictated by the neuroblastoma component in a fashion similar to that of adult neuroblastomas and responded to the chemotherapeutic regimen designed for treating neuroblastoma. The neuroblastoma component proved to be more aggressive than the other elements of this neoplasm. This finding suggests that mixed germ cell tumors showing a large neuroblastoma component should be treated promptly and aggressively with chemotherapy.

Disordered differentiation as a target for novel approaches to the treatment of neuroblastoma

Some childhood malignant neoplasms are thought to arise in embryonic tissues. These tumors present unique opportunities for studying the maturation of specific cellular lineages and examining the possible role of alterations in the regulation of differentiation in tumor development. Several features of neuroblastoma, a tumor thought to arise in cells originating in the embryonic neural crest, suggest that it may be particularly useful in this regard. The identification of a series of markers that characterize the various cell types of the peripheral nervous system that are detectable in neuroblastoma tumor tissues has made it possible to recognize that the cells of neuroblastoma tumor cell lines and tissues correspond to specific stages of adrenal gland development. Experiments directed at understanding the cellular signals by which neural crest cell maturation is mediated may provide insights of therapeutic import because neuroblastoma tumors corresponding to some stages of differentiation respond very differently to nonspecific cytotoxic therapies than tumors corresponding to other stages.

Clinical and biologic features in the prognosis and treatment of neuroblastoma.

Recent advances in the management of neuroblastoma have their basis in an increasing understanding of the biologic diversity that typifies these tumors. Current therapy is defined by risk of disease progression or relapse and has become best delineated in lower-stage disease and in infants. Older children with disseminated disease continue to exhibit very poor overall outlook, despite recent advances in dose-intensive chemotherapy. This review updates the clinical and biologic features of neuroblastoma that have a significant impact on prognosis and therapeutic design and discusses recent trends and controversies in the treatment of specific subsets of patients.

Proposal and Assessment of Japanese Tumor Node Metastasis Postsurgical Histopathological Staging System for Neuroblastoma Based on an Analysis of 495 Cases

In 1971, the Japanese Society of Pediatric Surgeons' Committee on Malignancies proposed new criteria for neuroblastoma staging. It was fundamentally, based on the system of Evans et al. described in 1971. The main difference was the separation of stage IV disease into stages IV-A, with metastases to bone, orbita, distant lymph nodes and viscera other than liver, IV-B, the primary tumor extending over the midline and with metastases to bone marrow, liver and skin, and IV-S, which was the same as that of Evans et al. The new criteria did not include the resectability of the primary tumor, assessment of regional lymph node involvement or any other disease assessment resulting from therapeutic intervention. For the purpose of international usage, the Japanese system has been newly formulated and proposed as the Japanese Tumor Node Metastasis (TNM) Postsurgical Histopathological Classification for Neuroblastoma. In the present report, 495 neuroblastomas, registered between 1970 and 1985, were analyzed retrospectively according to the International Union Against Cancer (UICC) TNM classification and the proposed Japanese TNM system. The analyses suggested that the Japanese system reflected both the extent of tumor invasion and its biological neuroblastoma characteristics better than the UICC TNM classification based on statistical analysis.

Establishment and characterization of a primitive neuroectodermal tumor of bone continuous cell line (LAP‐35)

A continuous tumor cell line (LAP-35) was established from a primitive neuroectodermal tumor of bone from the right tibia of a 12-year-old female. The neural character of the cell line was documented by the spontaneous growth of neurites and by the presence of several neural markers, including neuron-specific enolase (NSE), S-100 protein, neurofilaments, chromogranin A, synaptophysin and positivity to monoclonal antibodies UJ127.11, UJ13A, UJ181.4. Cell-sorter analysis showed a high expression of nerve growth factor receptor (NGFr) and major histocompatibility complex class I-related molecules. A unique cytogenetic profile was observed, including a reciprocal chromosomal translocation (rct) 11:22 (q24;q12), typically associated with Ewing's sarcoma and neuroepithelioma, and deletion of the short arm of chromosome 1 (lp-), otherwise a feature of neuroblastoma. N-myc proto-oncogene was neither amplified nor expressed, whereas the expression of c-myc was documented by northern blot analysis. These features distinguish this new cell line from previously reported neuroectodermal cell lines, identifying LAP-35 as a unique model of a group of neural bone tumors that share characteristics of neuroblastoma as well as neuroepithelioma.

Neuroblastoma, an under-diagnosed tumour: a 7-year experience in Zaria

The features of neuroblastoma and outcome of its management in 15 Nigerian children seen in the Ahmadu Bello University Teaching Hospital, Zaria over a 7-year period are described. The majority were between the ages of 3 and 5 years and the male:female ratio was 2.75:1. Over half of the patients presented with abdominal masses, about half with proptosis and a third with skull nodules. The diagnosis of neuroblastoma was correctly made on admission in only five instances. The mainstay of treatment was chemotherapy and the outcome was uniformly poor. Only one patient attended follow-up for as long as 1 year. Based on the present study, the frequency of neuroblastoma ranks third, after Burkitt's lymphoma and Wilms' tumour, amongst malignant childhood solid tumours encountered in the paediatric unit of Ahmadu Bello University Teaching Hospital. The low index of suspicion and poor diagnostic facilities might, however, have contributed to the low reported incidence, late diagnosis and poor survival rates of children with this tumour.

Three cholinergic neuroblastoma hybrid cell lines that form few synapses on myotubes are deficient in acetylcholine receptor aggregation molecules and large dense core vesicles

Three neuroblastoma × glioma hybrid cell lines that synthesize and release acetylcholine but that form few or no synapses with cultured skeletal muscle cells lack two characteristics of neuroblastoma or hybrid cell lines that do form many synapses with myotubes: large dense core vesicles and the ability to increase the number of nicotinic acetylcholine receptor clusters on co-cultured myotube membranes. Functional synapse formation on myotubes was increased by co-culturing myotubes and cells from one of the defective lines with neuroblastoma cells that induce myotube acetylcholine receptor aggregation but which synthesize little or no acetylcholine.