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Neurological complications of cancer are some of the most feared manifestations of malignant disease. Their frequency is increasing with improvements in the treatment of primary systemic disease. This article discusses the approach to patients with neurological complications of cancer and reviews some of the most common causes.
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Despite aggressive therapy, many nervous system neoplasms, including malignant gliomas, medulloblastomas, malignant meningiomas, and neurofibrosarcomas, maintain high mortality rates. The authors recently utilized a thymidine kinase-negative herpes simplex-1 mutant virus, dlsptk, with reduced neurovirulence, for the effective treatment of malignant human gliomas in cell culture and in nude mouse in vivo models. The range of human nervous system tumors that might be responsive to viral therapy is now expanded. Three medulloblastoma, four malignant or atypical meningioma, and five neurofibrosarcoma cell lines or early-passage tumors were treated with the dlsptk virus in cell culture. A cell death rate of at least 99% was evident in every tumor tested for at least one multiplicity of infection within 14 days after treatment. Control tumor cell cultures remained viable. To test dlsptk therapy in vivo, the authors treated human medulloblastoma subcutaneous xenografts with two doses of dlsptk. Mean growth ratios were significantly inhibited in the treated group when compared to control tumors, and there was a significant number of tumor regressions in the treated animals. Similar results were seen with human malignant meningioma xenografts in a subrenal capsule study. These results encourage the further investigation of viral therapy in the treatment of a broad spectrum of nervous system tumors refractory to conventional treatment methods.
Formalin-fixed, paraffin-embedded surgical specimens from 137 primary central nervous system tumors, including 26 astrocytomas (21 fibrillary, 1 protoplasmic, 1 gemistocytic and 3 pilocytic), 26 anaplastic astrocytomas, 9 glioblastomas, 1 gliosarcoma, 8 oligodendrogliomas, 4 ependymomas, 1 anaplastic ependymoma, 2 subependymomas, 3 paragangliomas, and 57 meningiomas, were immunostained with the CM1 polyclonal (pAb) and the DO-7 monoclonal (mAb) antibodies against the p53 protein, using the streptavidin/peroxidase method. In addition, two series of 17 and 9 medulloblastomas were also immunostained with the above pAb and mAb, respectively. p53 protein expression was observed in 7 fibrillary astrocytomas, 17 anaplastic astrocytomas, 5 glioblastomas, 1 gliosarcoma, 1 oligodendroglioma, 1 anaplastic ependymoma, and 4 meningiomas with the CM1 pAb. An additional 10 cases (i.e., 3 anaplastic astrocytomas and 7 meningiomas) were found to be p53 protein positive with the DO-7 mAb. Of the medulloblastomas, 8 (of the 17) and 4 (of the 9) were found to express p53 protein with CM1 pAb and DO-7 mAb, respectively. Our results indicate that p53 protein is expressed in a number of central nervous system neoplasms, and suggest that in astrocytic tumors a possible association may exist between p53 protein expression and tumor progression through increasing histological grades of malignancy.
Fibrillary astrocytoma, the most common primary central nervous system neoplasm, is infiltrating, rapidly proliferating, and almost invariably fatal. This contrasts with the biologically distinct pilocytic astrocytoma, which is circumscribed, often cystic, slowly proliferating, and associated with a favorable long-term outcome. Diagnostic markers for distinguishing pilocytic astrocytomas from infiltrating anaplastic astrocytomas are currently not available. To identify genes that might either serve as markers or explain these distinct biologic behaviors, cDNA microarray analysis was used to compare the expression of 7,073 genes (nearly one quarter of the human genome) between these 2 types of astrocytoma. Messenger RNAs pooled from 3 pilocytic astrocytomas and from 4 infiltrating anaplastic astrocytomas were compared. Apolipoprotein D (apoD), which expressed 8.5-fold higher in pilocytic astrocytomas, showed the greatest level of differential expression and emerged as a potential marker for pilocytic tumors. By immunohistochemistry, 10 of 13 pilocytic astrocytomas stained positively for apoD, while none of 21 infiltrating astrocytomas showed similar staining. ApoD immunostaining was also seen in 9 of 14 of gangliogliomas, 4 of 5 subependymal giant cell astrocytomas (SEGAs), and a single pleomorphic xanthoastrocytomas (PXAs). By in situ hybridization, pilocytic astrocytomas, in contrast with infiltrating astrocytomas, showed widespread increased apoD expression. SAGE analysis using the NCBI database showed a higher level of expression of apoD RNA in pilocytic astrocytoma than in any of the other 94 neoplastic and non-neoplastic tissues in the database. ApoD is associated with decreased proliferation in some cell lines, and is the protein found in highest concentration in cyst fluid from benign cystic disease of the breast. ApoD might play a role in either decreased proliferation or cyst formation in pilocytic astrocytomas, gangliogliomas, SEGAs, and PXAs.
An association between central nervous system neoplasm and pregnancy is uncommon although its frequency is underestimated. The most commonly observed tumors are acoustic neuromas, meningiomas and gliomas. The interactions between these tumors and pregnancy is not well known : Pregnancy could affect tumor growth by : - activating tumor growth by stimulating receptors; - increasing the peritumoral edema; - favoring immunotolerance due to pregnancy. Steroid hormone receptors and their therapeutic significance are described here, focusing particularly in meningiomas. Central nervous system tumors do not effect the progress of pregnancy per se but do the therapeutic implications. The clinical aspects are the same as in non-pregnant women. MRI appears to be the most adapted imaging technique. Neurosurgical guidelines are also described, with emphasis on symptomatic therapeutics, especially for seizure. Attitudes concerning the nature of the tumor and time of pregnancy are then discussed. The obstetrical attitude should be therapeutic abortion or delivery, with cesarean if necessary. Prognosis is getting better for the child and mother alike, but still remains poor.
Although the treatment of central nervous system neoplasms generally is unrewarding, some animals with spinal neoplasia may, for a variety of reasons, be successfully managed for extended periods of time. The veterinary profession has greater experience with spinal surgery than with intracranial surgery. As a result, surgeons are more willing to attempt and more successful at removing or debulking spinal neoplasms. Additionally, there are more affordable and accessible diagnostic procedures available to evaluate the spinal cord than there are to evaluate the brain. Finally, the majority of tumors that affect the spinal cord are extramedullary and are therefore amenable to attempts to remove them surgically.
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We used the nation-wide Swedish Family-Cancer Database to analyse the risk of nervous system tumours, leukaemia and non-Hodgkin's lymphoma in age groups 0-4 and 0-19 years among Swedish-born offspring of immigrants. The study included 850 000 individuals with an immigrant background, including European, Asian and American parents. We calculated standardised incidence ratios for the above three malignancies using Swedish offspring as a reference. Subjects were grouped by region or by selected countries of parental origin. No group differed significantly from Swedes in the occurrence of nervous system neoplasm or leukaemia. Offspring of Yugoslav fathers (SIR 2.27) and Turkish parents were at increased risk of non-Hodgkin's lymphoma. The highest risk was noted for non-Hodgkin's lymphoma among young offspring (0-4 years) of two Turkish parents (6.87). The currently available limited data on rates for childhood non-Hodgkin's lymphoma in these countries do not explain the risk in the offspring of immigrants. Yugoslavs and Turks are recent immigrant groups to Sweden, and their offspring have been subject to much population mixing, perhaps leading to recurring infections and immunological stimulation, which may contribute to their excess of lymphomas.
INTRODUCTION: Pediatric intramedullary spinal cord tumors are rare and make up only a small percentage of all central nervous system neoplasms. DISCUSSION: These neoplasms are predominantly benign histologically, regardless of size, with a large percentage being astrocytomas or gangliogliomas. Ependymomas, which are common in adults, are relatively uncommon in children. Contemporary management of these tumors has generated much controversy. These neoplasms occur primarily in the cervical region, with pain or a motor deficit as the chief complaint. Surgery on these neoplasms can safely be performed using modern surgical adjuncts such as the ultrasonic aspirator, contact laser and neurophysiological monitoring. A radical resection of these tumors results in a good long-term outcome, since the majority are histologically benign. Adjuvant radiation therapy should only be administered for high-grade or malignant tumors. CONCLUSION: The majority of spinal cord tumors are benign; however, malignant tumors have a dismal outcome and surgery in these children should be limited to a conservative debulking. An attempt should be made for radical surgery in hope of avoiding radiation and chemotherapy for the benign tumors. Spinal deformity is a concern in these patients since 35% of children may require a stabilization procedure.
Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant central nervous system neoplasm that usually affects very young children and is typically deadly despite very aggressive treatment. Considered rare, the tumor was not recognized as a distinct entity until the 80's, due to its similar features with other primitive tumors. Although AT/RT has become increasingly recognized, published data has been based on small series and are retrospective. Based on these data, there are occasional long-term survivors, most of whom received intensive multi-modal therapy. AT/RT is the first pediatric brain tumor for which a candidate tumor suppressor gene has been identified. A mutation or deletion in the INI1 gene occurs in the majority of AT/RT tumors. The function of the gene is not yet understood. Prospective clinical and biologic trials are greatly needed to understand the efficacy of therapeutic interventions, as well as the role of the gene.
Significant advances in the treatment of medulloblastoma and primitive neuroectodermal tumors have been made in the past three decades. Maximal surgical resection is a mainstay of therapy. However, unlike many other central nervous system neoplasms, medulloblastoma and primitive neuroectodermal tumors are radiation and chemotherapy responsive. Despite this response, the prognosis for patients with these tumors remains variable and is relatively poor in infants and patients with metastatic disease. These tumors most commonly arise in children, thus most clinical trials emphasize the reduction of long-term sequelae, in addition to improving survival. All newly diagnosed patients who are eligible should be offered participation in a clinical trial. If a patient is ineligible or declines consent/assent for a clinical trial, the best current treatment approach is surgical resection, followed by radiation therapy (except for children younger than 3 years) with weekly vincristine. For high-risk patients, 36 Gy of craniospinal irradiation should be delivered plus a boost of 19.8 Gy to the posterior fossa/primary tumor bed and sites of bulk metastatic disease. For average-risk patients, the craniospinal irradiation dose may be lowered to 23.4 Gy plus 32.4 Gy to the posterior fossa/tumor bed. After radiation therapy, intensive multimodal chemotherapy should be used for all patients.
Central neurocytomas are rare central nervous system neoplasms. Since the first description, approximately 500 cases of these tumors have been published to date. Nevertheless, only a limited number of genetic studies on these tumors have been reported. Here we investigated 20 "typical" central neurocytomas using array-based comparative genomic hybridization (array-CGH) with the GenoSensor Array 300. The functional significance of detected chromosomal aberrations harboring potent candidate genes was also examined at the mRNA expression level. Each tumor examined displayed DNA copy-number aberrations (CNAs), and mean number of CNAs per tumor was 38.1 +/- 7.1 (range 19-53). Frequent gains were mapped at 2p24.1-22.1, 10q23.3-26.3, 11q23-25, and 18q21.3-qter. Frequent losses were identified at 1pter-36.3, 1p34.3, 6q13-21, 12q23-qter, 17p13.3, 17q11-23, and 20pter-12.3. There were 10 gained and 23 lost single DNA clones affecting >or=40% of samples tested. mRNA expression levels of 24 selected candidate genes harbored in these imbalanced clones were analyzed. MYCN, PTEN, and OR5BF1 were strongly overexpressed, whereas BIN1, SNRPN, and HRAS were found to be strongly underrepresented at the transcriptional level. Thus these data support that MYCN oncogene gain/overexpression accompanied by reduced expression of BIN1 tumor suppressor may contribute to central neurocytoma tumorigenesis.
Alterations of the p53 protein, which is a 53 kD phosphoprotein and gene product of the p53 gene, has been found to play a major role in the genesis of a variety of human malignancies including tumors of the central nervous system. We investigated 50 tumor specimens from primary central nervous system neoplasms. Tissue samples were screened for mutations by the single-strand conformation polymorphism method and detected mutations were sequenced. All tissue specimens were stained immunohistochemically for p53 protein, which when altered accumulates in the nucleus due to prolonged half-life. Mutations were found in six cases, including one pilocytic astrocytoma World Health Organization (WHO) grade I, two astrocytomas WHO grade II, two anaplastic astrocytomas WHO grade III, and one primitive neuroectodermal tumor (PNET). In terms of relative frequency mutations were found mostly in the group of anaplastic astrocytomas WHO grade III. Interestingly, no mutations were found in the group of investigated glioblastomas. P53 immunopositivity did not correlated with the mutations found, whereas the staining index was significantly higher in the cases with detected mutations than in those without. When p53 alterations is seen as an indicator for different pathogenic pathways in glioma formation, this study gives evidence for a difference between anaplastic astrocytoma and glioblastoma. However, since there was a great overlap in p53 immunopositivity and p53 mutation in tumors of different WHO grades and entities, it seems that p53 will not act as a marker molecule neither for tumor entities nor for tumor malignancy.
OBJECT: Pediatric low-grade gliomas (LGGs) are the largest group of central nervous system neoplasms in children. Although these tumors are generally benign, 5 to 10% of patients with pediatric LGGs present with leptomeningeal dissemination. The genetic and biological nature of these tumors is poorly understood. The authors looked for certain molecular abnormalities that may differentiate disseminated gliomas from the other pediatric LGGs. METHODS: Comparative genomic hybridization (CGH) was applied to 18 pediatric LGGs. Six cases featuring disseminated pediatric LGGs were compared with 12 control cases involving nondisseminated pediatric LGGs. Fluorescence in situ hybridization (FISH) analysis and immunohistochemical analysis were used to highlight further specific genetic targets. The CGH revealed multiple chromosomal abnormalities in five of six cases with disseminated gliomas and in six of 12 control cases. No correlation was found between the number of chromosomal abnormalities and dissemination status. Amplification of chromosome 7 was noted in four of six cases with disseminated gliomas as opposed to one of 12 control cases (p = 0.02). The FISH analysis revealed epidermal growth factor receptor (EGFR) amplification in one case negative to chromosome 7 amplification by CGH, raising the amplification cases to five of six (p = 0.0038). Immunohistochemical analysis for EGFR was positive in six of six cases and in two of 12 control cases (p = 0.0015). At the end of a mean follow-up period of 7.2 years, all patients with disseminated gliomas are alive with variable but slow disease progression. CONCLUSIONS: The high rate of EGFR gene amplification and protein expression in disseminated pediatric LGGs is intriguing and may have implications for our understanding of the role of EGFR in glioma genesis. Targeted therapies may be available for these children. Larger-scale studies are needed to establish further these findings.
Meningiomas are common central nervous system neoplasms that exhibit remarkably diverse histopathology and biological behavior. Compared to astrocytomas, the most common central nervous system tumor, little is known about the molecular pathways critical for meningioma tumor formation and malignant progression. As an initial step toward characterizing the genetic basis of meningioma pathogenesis, we assessed cancer-related gene expression profiles of nonneoplastic leptomeningeal specimens and human meningiomas of varying World Health Organization (WHO) grade using high-density oligonucleotide microarrays. Although expression profile differences between nonneoplastic and meningioma specimens were readily discernible, the expression profile of a subset of genes could also distinguish WHO grade I from WHO grades II and III tumors. Altered expression levels of several genes identified in this study have been previously noted in meningiomas (eg, growth hormone receptor, IGFBP-7, endothelin receptor A, IGF2). However, we also identified a number of novel genes whose expression was associated with WHO grade and was confirmed by reverse transcriptase-polymerase chain reaction in a larger, independent set of meningeal tumors (n = 47). This report represents the first gene expression profiling studies of meningiomas and identifies some initial candidate genes that may provide further insights into the genetic basis for meningioma pathogenesis.
The most common human immunodeficiency virus-related (HIV) malignancies to date include Kaposi's sarcoma and the high-grade non-Hodgkin's lymphomas. There also appears to be an association between HIV and an aggressive form of Hodgkin's disease. In addition, there is a spectrum of HIV-related central and peripheral neurologic syndromes. This article documents four patients with HIV-associated lymphoma who presented with peripheral neurologic syndromes as part of their neoplastic process. Autopsy results obtained from two of these patients showed direct nerve infiltration by lymphoma. All patients had an elevated serum lactate dehydrogenase (LDH). It is recommended that HIV-related lymphoma be considered in a high-risk patient who presents with a peripheral neurologic syndrome especially if there is an elevated serum LDH.