Julianne Behnke

C-MYC expression in medulloblastoma and its prognostic value

To identify prognostic factors in medulloblastoma, a common malignant brain tumor of childhood, expression of the oncogene c‐myc was examined at the mRNA level by in situ hybridization. c‐myc mRNA expression was observed in 30 of 72 tumors (42%). The c‐myc gene copy number was determined by quantitative PCR from genomic DNA of paraffin‐embedded tumors. c‐myc gene amplification was present in 5 of 62 cases (8.3%). Therefore, c‐myc amplification was obviously not the cause of c‐myc mRNA expression in most samples. Kaplan‐Meier estimation revealed a significant correlation between c‐myc mRNA expression and survival (total mean follow‐up 4.6 ± 3.6 years, log‐rank p = 0.02). Multivariate logistic regression analysis including sex, age, histological type, degree of surgical resection and expression of synaptophysin, GFAP and c‐myc, was carried out on 54 patients who received both radiotherapy and chemotherapy. The analysis identified expression of c‐myc as an independent predictive factor of death from disease. Int. J. Cancer 89:395–402, 2000.

Distribution of epidermal growth factor receptor gene amplification in brain tumours and correlation to prognosis.

In 75 gliomas and 31 meningiomas, mutations at the epidermal growth factor receptor (EGFR) gene locus were restricted to gliomas. The ligands of this receptor, epidermal growth factor and transforming growth factor alpha, lacked quantitative changes at their loci in gliomas and meningiomas. EGFR gene amplification occurred in astrocytomas, oligodendrogliomas, ependymomas and glioblastomas. The frequency of this mutation significantly increased with the malignancy grade and the patients age. Especially in glioblastomas of individuals aged over 64 years, EGFR gene mutations were observed without chromosome-10-specific allele losses. This finding contradicts the hypothesis that deletion of one entire chromosome 10 regularly precedes EGFR gene amplification in primary glioblastomas of patients aged over 50 years. It was found that most individuals whose gliomas carry an EGFR gene mutation have a poor prognosis, comparable to that of glioblastoma patients even when the tumour is graded as benign.

c-myc oncogene family expression in glioblastoma and survival

BACKGROUND In gliomas, c-myc proto-oncogene expression has been found to correlate with the grade of malignancy, with low expression in Grade I and II and high expression in Grade III and IV tumors. We aimed to discover if myc expression is of prognostic significance in glioblastomas. METHODS Expression of the c-myc, N-myc, and L-myc proto-oncogenes and of the max gene was investigated in 46 supratentorial glioblastomas from adult patients using in situ hybridization. RESULTS Seventy-eight percent of the tumors expressed c-myc m-RNA, 84% max m-RNA, 57% N-myc m-RNA, and 57% L-myc m-RNA. The postoperative survival of patients over 60 years of age and that of patients under 60 years of age were analyzed separately, since advancing age was found to be negatively correlated with the duration of postoperative survival (p = 0.004). There was no significant difference in postoperative survival in either age group between patients whose tumors expressed either c-myc, N-myc, or L-myc, respectively, and those whose tumors did not exhibit this characteristic. A difference in postoperative survival, however, was found in the over 60-year age group between patients whose tumors expressed max to an equal or lesser extent than c-myc and those whose tumors expressed max to a greater extent than c-myc or neither max nor c-myc. CONCLUSION The biologic behavior of glioblastomas in older patients may depend on the relative, but not on the absolute content of the c-myc protein and interacting proteins.

Potential prognostic value of C-erbB-2 expression in medulloblastomas in very young children.

Purpose The expression of the c-erbB-2 oncogene was studied in childhood medulloblastoma to evaluate its prognostic value, which has been claimed previously. Patients and Methods Tumor material from 45 patients <15 years old at diagnosis was studied using 3 monoclonal antibodies against the internal and external domains of the c-erbB-2 oncogene product. Results Six of the 45 (13%) tumor specimens were found to be positive. C-erbB-2 expression was found more often in patients <3 years old at diagnosis (4 of 15 patients, 27%) than in older patients (2 of 30, 6.6%). During the follow-up period (5.8±2.8 years) all patients with c-erbB-2 expression died of disease (after 1.2±0.7 years). Kaplan-Meier estimation revealed a highly significant correlation of c-erbB-2 expression and survival (p = 0.002). A further study of the expression of synaptophysin and the glial fibrillary acidic protein (GFAP) in the 45 tumors revealed a negative correlation of the expression of c-erbB-2 and these proteins. Conclusion C-erbB-2, which may be predominantly expressed by less differentiated tumors, was found to delineate a poorer prognostic subgroup, especially when diagnosed in patients <3 years old.

Immunohistochemistry of primary central nervous system malignant rhabdoid tumors: report of five cases and review of the literature

Abstract Malignant rhabdoid tumors (MRT) are characterized by a typical light microscopic morphology with uniformly round tumor cells, vacuolated cytoplasm with occasional round, hyaline intracytoplasmic, periodic acid-Schiff-positive inclusions, vesicular nuclei with prominent nucleoli and positive immunoreactivity for vimentin. The histogenesis of MRT is controversial. Five cases of primary central nervous system (CNS) rhabdoid tumors in children are presented. Immunohistochemical, light and electron microscopic features are compared with primary CNS malignant rhabdoid tumors reported in the literature. Expression of various neurofilaments in our cases of primary CNS rhabdoid tumors was prominent and we therefore favor a neural differentiation of extrarenal intracerebral rhabdoid tumors.

Treatment of primary malignant rhabdoid tumor of the brain : Report of three cases and review of the literature

PURPOSE Primary malignant rhabdoid tumor (MRT) of the central nervous system is an extremely aggressive tumor predominantly related to early childhood, with characteristic histopathological findings but unclear histogenesis. Owing to its low incidence, little knowledge exists concerning the best therapeutic strategy. METHODS AND MATERIALS Three children of our hospital with MRT of the brain underwent a maximum tumor resection followed by multidrug chemotherapy and radiation therapy to the craniospinal axis. RESULTS Relapse was disseminated along the spinal subarachnoid spaces in one child and occurred at the primary tumor site in the other two patients. Maximum survival was 15 months from diagnosis. CONCLUSION A review of patients reported in the literature and a comparison to our patients reveals a high propensity to early local relapse and meningeal dissemination. In the absence of more effective therapeutic options, we recommend multidisciplinary treatment of patients in good general condition and with resectable disease. In particular, following radiation therapy, tumor remissions and delay of tumor regrowth have been observed.

Proliferative potential of human brain tumours as assessed by nucleolar organizer regions (AgNORs) and Ki67-immunoreactivity

SummaryTwo proliferation markers, silver stained nucleolar organizer regions (AgNOR) and immunoreactivity with Ki-67, were used to assess the proliferative activity in 80 smear preparations from neurosurgically removed intracranial tumours. These included 45 gliomas, 18 meningiomas, 8 metastases and 9 others. We found a remarkably close correlation between the results obtained with both methods. Increasing malignancy, as determined by conventional grading, was paralleled by an increase in the growth fraction and the number of nucleolar organizer regions. Linear regression analysis yielded the following equation: AgNORs/cell=0.35 × L1 (Ki-67) + 3.24, with a correlation coefficient of rs=0.53 (Spearman rank correlation test, p<0.0001). Thus, both the Ki-67 L1 and the AgNOR technique appear suitable for estimating the proliferative potential in smear preparations of human intracranial neoplasms. The AgNOR technique may be particularly useful for application to stereotaxic biopsies since it can easily be performed on minute tumour samples.

Intra-axial endophytic tumors in the pons and/or medulla oblongata I. Symptoms, neuroradiological findings, and histopathology in 30 children

Abstract Between August 1987 and June 1994 we operated upon 30 consecutive children suffering from endophytic intra-axial tumors located in the pons and/or medulla oblongata. We present the clinical findings, neuroradiological aspects and histopathological results recorded in these cases. Diagnostic tests included clinical examinations, neurophysiological tests and neuroradiological imaging [magnetic resonance tomography (MRT) in all cases, often combined with cranial computer tomography (CCT)]. The diagnosis was confirmed by histopathological examination of the tumor material obtained by open surgical exploration in all cases. We conclude that a short history and more horizontal growth within the pons are more valuable predictors of the histopathology than dif-ferentiation between focal or diffuse growth patterns. MRT has little predictive value for histopathological diagnosis in intra-axial brain stem tumors.

Intra-axial endophytic tumors in the pons and/or medulla oblongata. II. Intraoperative findings, postoperative results, and 2-year follow up in 25 children.

Abstract Between July 1987 and June 1994 we operated upon 30 consecutive children suffering from endophytic intra-axial tumors located in the pons and/or medulla oblongata. The 25 children operated on between July 1987 and October 1993 whose postoperative course could be assessed for a minimum of 2 years after operation were included in this study. Operability of a brain stem tumor was shown to be independent of its size. A gross tumor resection between 80% and 100% could be performed in half these cases, and subtotal or partial resection in the other half. The radicality of resection was not influenced by tumor histopathology, but was dependent on intraoperative findings relating to its consistency, infiltration, and visibility. On follow up, 15 of the 25 children were found to have died within the period of 2 years. Two children died in the immediate postoperative period (at 2 days and 2 weeks after surgery), of acute brain stem swelling and an unsuspected bleeding disorder, respectively. The other 13 of these 15 children died of tumor progression between 1 and 19 months after operation, with a median survival time of 9 months. In the group of the surviving 10 children the histopathology was grade I astrocystoma in 6 cases, angioma in 2 cases, and grade II oligodendroglioma and grade II ependymoma in 1 case each. Postoperatively, most of the children showed some increase in their preoperative deficits, but recovered after 2–3 months. After 2 years, 10 of the 25 children who were followed up are alive and 9 of them attend regular school or kindergarten.

Amplification of the c-erbB oncogene is associated with malignancy in primary tumours of neuroepithelial tissue.

SummaryIn various primary brain tumours of neuroepithelial tissue recombinant DNA techniques were used to demonstrate changes of the epidermal growth factor receptor gene, which is homologous to the c-erbB oncogene. Twenty-one of 40 grade III/IV tumours, but only 1 of 16 grade I/II tumours were found to contain amplified and/or rearranged c-erbB sequences. This highly significant difference suggest that c-erbB amplification, rearrangement, or both, are important steps in malignant transformation in a subset of patients with neuroepithelial tumours.