Medulloblastoma: histopathologic and molecular markers of anaplasia and biologic behavior (original) (raw)
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Journal of Clinical Oncology, 2004
To assess the feasibility of performing central molecular analyses of fresh medulloblastomas obtained from multiple institutions and using these data to identify prognostic markers for contemporaneously treated patients. Ninety-seven samples of medulloblastoma were collected. Tumor content in samples was judged by frozen section review. Tumor ERBB2 protein and MYCC, MYCN, and TRKC mRNA levels were measured blind to clinical details using Western blotting and real-time polymerase chain reaction, respectively. Histopathologic and clinical review of each case was also performed. All data were subjected to independent statistical analysis. Sample acquisition and analysis times ranged from 3 to 6 days. Eighty-six samples contained sufficient tumor for analysis, including 38 classic, 30 nodular desmoplastic, and 18 large-cell anaplastic (LCA) medulloblastomas. Protein and mRNA were extracted from 81 and 49 tumors, respectively. ERBB2 was detected in 40% (n=32 of 81) of tumors, most frequently in LCA disease (P=.005), and was independently associated with a poor prognosis (P=.031). A combination of clinical characteristics and ERBB2 expression provided a highly accurate means of discriminating disease risk. One hundred percent (n=26) of children with clinical average-risk, ERBB2-negative disease were alive at 5 years, with a median follow-up of 5.6 years, compared with only 54% for children with average-risk, ERBB2-positive tumors (n=13; P=.0001). TRKC, MYCC, and MYCN expression and histopathologic subtype were not associated with prognosis in this study. Central and rapid molecular analysis of frozen medulloblastomas collected from multiple institutions is feasible. ERBB2 expression and clinical risk factors together constitute a highly accurate disease risk stratification tool.
Neuro-Oncology, 2014
were subjected to thorough histopathological investigation, CTNNB1 mutation analysis, quantitative PCr, MlPA and FISH analyses for cytogenetic variables, and methylome analysis. By univariable analysis, clinical factors (M-stage), histopathological variables (large cell component, endothelial proliferation, synaptophysin pattern), and molecular features (chromosome 6q status, MYC amplification, subgrouping) were found to be prognostic. Molecular consensus subgrouping (WNT, SHH, group 3, group 4) was validated as an independent feature to stratify patients into different risk groups. When comparing methods for the identification of WNT-driven medulloblastoma, this study identified CTNNB1 sequencing and methylation profiling to most reliably identify these patients. After removing patients with particularly favorable (CTNNB1 mutation, extensive nodularity) or unfavorable (MYC amplification) Abstract This study aimed to prospectively evaluate clinical, histopathological and molecular variables for outcome prediction in medulloblastoma patients. Patients from the HIT2000 cooperative clinical trial were prospectively enrolled based on the availability of sufficient tumor material and complete clinical information. This revealed a cohort of 184 patients (median age 7.6 years), which was randomly split at a 2:1 ratio into a training (n = 127), and a test (n = 57) dataset in order to build and test a risk score for this population. Independent validation was performed in a non-overlapping cohort (n = 83). All samples T. Pietsch, r. Schmidt, S. rutkowski and S. M. Pfister contributed equally.
Nature Clinical Practice Oncology, 2007
The information for this Review was compiled by searching the PubMed and MEDLINE databases for articles published until 19 December 2006. Electronic early-release publications were also included. Only articles published in English were considered. The search terms used included "medulloblastoma" in association with: "reviews", "pathogenesis", "tumorigenesis", "risk stratification", "risk assessment", "histopathology", "clinical management", "cytogenetics", "chromosomal instability", "molecular analyses", "molecular markers" and "gene array". Full articles were obtained and references were checked for additional material when appropriate. Chapters from the latest editions of textbooks were also reviewed and cited when appropriate.
Clinical and molecular stratification of disease risk in medulloblastoma
British journal of cancer, 2001
The accurate assessment of disease risk among children with medulloblastoma remains a major challenge to the field of paediatric neuro-oncology. In the current study we investigated the capacity of molecular abnormalities to increase the accuracy of disease risk stratification above that afforded by clinical staging alone. 41 primary medulloblastoma tumour samples were analysed for ErbB2 receptor expression using immunohistochemistry, and for aberrations of chromosome 17 and amplification of the MYC oncogene using fluorescence in situ hybridisation. The ErbB2 receptor and deletion of 17p were detected in 80% and 49% of tumours, respectively. 17p loss occurred either in isolation (20%), or in association with gain of 17q (29%), compatible with an isochromosome of 17q. Amplification of MYC was detected in only 2 tumours. Significant prognostic factors included, 'metastatic disease' (P = 0.0006), 'sub-total tumour resection' (P = 0.007), 'high ErbB2 receptor express...
Histopathologic grading of adult medulloblastomas
Cancer, 2007
BACKGROUND. Histopathologic evaluation of the degree and extent of anaplasia is a useful prognostic parameter in pediatric medulloblastomas. Whether the same applies to adult medulloblastomas is not known.
Cancer, 1971
Medulloblastoma has invariably been associated with a poor prognosis. However, it has been shown that such tumors in adults have a slightly better prognosis than in children. We have studied 201 such neoplasms and attempted to correlate survival with several factors. In our series, adults survived longer (average 50 months) than children (average 11 months), and females (average 31 months) slightly longer than males (21 months). Location of the primary tumor was also of significance since patients with neoplasms primarily located in a cerebellar hemisphere showed a better survival (47 months) than those located in the cerebellar midline (17 months). T h e histologic typing of the tumor was also important. Patients with ''desmoplastic" medulloblastomas had an average survival of 51 months, while those with the "classical" medulloblastomas had an average of 18 months only. T h e majority of the desmoplastic neoplasms occurred in adults and in cerebellar hemispheres rather than the midline. Further differentiation within the tumor toward the neuroblastic or the glial lines was evident in 51 neoplasms, and no significant differences in survival were noted among them. Four patients eventually developed extracranial metastases, and two were associated with meningiomas. INCE BAILEY AND CUSHING, IN 1925,s DIS-S tinguished the medulloblastoma as a specific entity, a voluminous literature has accumulated on that subject with about 1,500 cases reported'J.23,27 and at least one book entirely devoted to it." Many authors studied the different factors affecting the prognosis of this neoplasm. These efforts were mainly concentrated on the methods of therapy7J0Jal 20.24.31.32 and age of onset.38.40.41 However, no serious attempts were made to correlate survival data with the morphology of medulloblastoma. In 1964, Rubinstein and Northfield38 subclassified the medulloblastoma into two main categories, the "classical" and the "desmoplastic" with a transitional form. Also, it has been reported that this neoplasm may differentiate into the glial or the neuroblastic line.2J'J1.22.39 The purpose of this paper is to examine the effects of age, sex, location of tumor, and particularly histologic variants on the prognosis of medulloblastoma.
“Large Cell/Anaplastic” Medulloblastomas: A Pediatric Oncology Group Study
Journal of Neuropathology & Experimental Neurology, 2000
495 medulloblastomas (MBs) from 6 Pediatric Oncology Group (POG) protocols were reviewed to assess the incidence and prognostic significance of ''large cell'' and ''anaplastic'' variants. ''Large cell'' medulloblastomas (LC MBs) were those with focal or diffuse, large, round neoplastic cells with prominent nucleoli. ''Anaplastic'' MBs (A MBs) were those with nuclei that were also large but markedly atypical with coarse chromatin and irregular shapes. Twenty-one cases were identified in the combined LC/A MB group, comprising about 4% of all MBs. Survival curves and Kaplan-Meier estimates of survival probabilities were examined separately for the LC/A MB and control groups. The logrank test for detecting poorer survival in the 21 cases was significant (p Ͻ 0.0001). Fluorescence in situ hybridization for c-myc showed amplification in 4 of 11 cases of the LC/A phenotype and 1 additional case of high level gain at 8q24 was disclosed by comparative genomic hybridization. Comparative genomic hybridization confirmed c-myc amplification and found evidence for isochromosome 17q in 3 of 4 LC/A cases studied successfully. One additional tumor showed high level gain restricted to 2p13 consistent with n-myc amplification. Monosomy 22, common in atypical teratoid/rhabdoid tumors, was not found. These results suggest that LC/A MB phenotype could be, at least in part, a correlate of c-myc, and possibly n-myc, amplification. The study thus confirms original observations about the LC MB in regard to histological features, immunohistochemical findings, c-myc amplification, cytogenetic findings, and poor prognosis.
Histopathologic grading of medulloblastomas
Cancer, 2002
Medulloblastomas are small cell embryonal tumors of the cerebellum found predominantly in children, only slightly more than half of whom survive. Predicting favorable outcome has been difficult, and improved stratification clearly is required to avoid both undertreatment and overtreatment. Patients currently are staged clinically, but no pathologic staging system is in use. Two rare subtypes at extreme ends of the histologic spectrum, i.e., medulloblastomas with extensive nodularity and large cell/anaplastic medulloblastomas, are associated with better and worse clinical outcomes, respectively. However, there is little data about correlations between histologic features and clinical outcome for most patients with medulloblastomas that fall between these histologic extremes of nodularity and anaplasia. Therefore, the authors evaluated the clinical effects of increasing anaplasia and nodularity in a large group of children with medulloblastomas, hypothesizing that increasing nodularity would predict better clinical outcomes and that increasing anaplasia would presage less favorable results.
Genetic Grouping of Medulloblastomas by Representative Markers in Pathologic Diagnosis
Translational Oncology, 2013
A recent analysis of the genetic features of medulloblastoma (MB) suggested classification into distinct subgroups according to gene expression profiles, including the Wingless signaling pathway-activated group (WNT group), the Sonic Hedgehog signaling pathway-activated group (SHH group), group 3, and group 4. To classify MB according to genetic features in practice, we analyzed 74 MBs using representative markers of each group. Based on immunohistochemistries (IHC), cytogenetic alterations, and a CTNNB1 mutation study, the patients were divided into the following three groups: cases showing nuclear β-catenin and/or CTNNB1 mutation and/or monosomy 6 were included in the WNT group (14/74, 18.9%); cases expressing GAB1 were included in the SHH group (15/74, 20.2%); cases that did not show positivity for markers of the WNT or SHH group were included in the non-WNT/SHH group (45/74, 60.6%). Immunoexpression of NPR3 seemed to lack sensitivity for classifying group 3, showing diffuse positivity in only two cases. KCNA1 was not specific to group 4 because it was expressed in all groups. Cases in the WNT group showed a slightly better survival than those in the SHH or non-WNT/SHH group, although additional cases are required for statistical significance. Isochromosome 17q (P = .002) and the large cell/anaplastic variant (P = .002) were demonstrated to be poor prognostic indicators in multivariate analysis. The representative IHC and cytogenetic data facilitated the division of MBs into the WNT and SHH groups; however, more specific markers should be added for the identification of group 3 and group 4 in practice.
Pathology - Research and Practice, 2004
The purpose of this study was to investigate whether quantitative assessment of cytologic anaplasia and angiogenesis may predict the clinical prognosis in medulloblastoma and stratify the patients to avoid both undertreatment and overtreatment. Medulloblastomas from 23 patients belonging to the Pediatric Oncology Group were evaluated with respect to some prognostic variables, including histologic assessment of nodularity and desmoplasia, grading of anaplasia, measurement of nuclear size, mitotic cell count, quantification of angiogenesis, including vascular surface density (VSD) and microvessel number (NVES), and immunohistochemical scoring of vascular endothelial growth factor (VEGF) expression. Univariate and multivariate analyses for prognostic indicators for survival were performed. Univariate analysis revealed that extensive nodularity was a significant favorable prognostic factor, whereas the presence of anaplasia, increased nuclear size, mitotic rate, VSD, and NVES were significant unfavorable prognostic factors. Using multivariate analysis, increased nuclear size was found to be an independent unfavorable prognostic factor for survival. Neither the presence of desmoplasia nor VEGF expression was significantly related to patient survival. Although care must be taken not to overstate the importance of the results of this single-institution preliminary report, pathologic grading of medulloblastomas with respect to grading of anaplasia and quantification of nodularity, nuclear size, and microvessel profiles may be clinically useful for the treatment of medulloblastomas. Further validation of the independent prognostic significance of nuclear size in stratifying patients is required.