Pediatric medulloblastoma: prognostic value of p53, bcl-2, Mib-1, and microvessel density (original) (raw)
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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.
Diagnostic markers in paediatric medulloblastoma: a Paediatric Oncology Group Study
Histopathology, 1999
We have reviewed immunohistochemically 17 paediatric medulloblastomas in order to determine if correlations exist that might be useful in subclassifying these tumours. Methods and results: The patient group included 11 children who had died (mean survival 13 months) and six still alive (followed for up to 10 years). Ten tumours were diffuse and six were nodular (one biopsy had only perivascular tumour). Of the 10 diffuse tumours, three were desmoplastic; of the six nodular tumours, all six were desmoplastic. All 17 tumours were synaptophysinreactive; three nodular tumours were glial fibrillary acidic protein (GFAP)-reactive in the nodules (two of three S100-reactive tumours were also GFAP-reactive). MIB-1 labelling indices (LI) ranged from 5 to 80%. Six tumours exhibited at least 1% LI against Tp53 (Mab D07 and/or Mab 1801). Eight cases were 100% bcl2reactive with nine cases having an LI <80% ('low labelling'). All nine 'low labelling' bcl2 cases were TP53 non-reactive; all six Tp53-reactive cases were bcl2 100% reactive. Six of 10 patients with diffuse medulloblastomas survived 18 months or less while four of 10 are alive up to 10 years. In contrast, five of six patients with nodular neoplasms died within 48 months of diagnosis with one patient followed up for less than 1 year. Conclusions: Immunohistochemistry is a useful adjunct in characterizing subsets of paediatric medulloblastomas and confirms that larger co-operative studies may be fruitful in identifying a prognostic utility of a combined histochemical/immunohistochemical analysis on these tumours.
Mitotic percentage index: a new prognostic factor for childhood medulloblastoma
European Journal of Cancer, 1997
We investigated the prognostic significance of a new method of mitotic figure quantitation, 'mitotic percentage index' (MPI), tumour S phase fraction (SPF) and DNA ploidy measured by flow cytometry, and various clinical prognostic factors including age, sex, tumour stage, degree of surgical resection, radiotherapy dose and adjuvant chemotherapy in 70 cases of childhood medulloblastoma diagnosed between 1968 and 1996. In univariate analysis, MPI (P < O.OOOl), posterior fossa radiotherapy dose (P= 0.003), tumour stage (P= 0.014), craniospinal radiotherapy dose (P= 0.019), year of diagnosis (P = 0.024) and SPF (P = 0.048) were significantly related to survival. In multivariate analysis, including tumour c-e&B-2 oncogene product expression, only MPI (P < O.OOOl), craniospinal radiotherapy dose (P = 0.003) and tumour stage (P = 0.035) retained independent prognostic significance, while age achieved significance (P = 0.039). A close relationship was observed between MPI and SPF (coeff = 0.8, P < 0.0001) and MPI and the percentage of tumour cells expressing the c-e&B-2 oncogene product (coeff = 0.416, PC 0.0001). This study has identified MPI as a new independent prognostic factor for childhood medulloblastoma. Its close relationship with tumour SPF confirms it as an accurate measure of tumour proliferation and its close relationship to expression of the c-e&B-2 oncogene supports a role for this growth factor receptor in the deregulation of normal mitogenic signal transduction in this malignancy.
Medulloblastomas in childhood: histological factors influencing patients' outcome
Child's Nervous System, 1987
Childhood treated from 1965 through 1981 were reviewed, and the correlation between histological findings of medulloblastomas and clinical course of the patients was studied. Thirty-five patients died but the remaining 30 are alive and without clinical evidertce of recurrence 5 years or more after surgery. Certain histological features on light microscopic examinations (e.g., pleomorphism of tumor cells; nuclear-cytoplasmic ratio, mitotic index, degree of vascularity and endothelial proliferation) do influence patient outcome with statistical significance (P<0.05). Thirty out of 65 medulloblastomas were examined further, using immunohistochemical methods with glial fib'rillary acidic protein (GFAP), neuron specific enolase (NSE), and factor VIII/vW factor (FVIII/vWF). GFAP stain was negative in 20%, NSE stain in 13.3% and F VIII/vWF stain in 16.7% of the medulloblastomas studied. "Desmoplastic" medulloblastomas showed a strong tendency toward positive NSE and GFAP staining in the glomerular portion. There was no correlation between patient outcome and the results of applied immunohistochemical studies. Our data indicate that certain histological features may influence patient outcome, but the degree and pattern of cellular differentiation do not predict outcome.
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.
Medulloblastoma: histopathologic and molecular markers of anaplasia and biologic behavior
Acta Neuropathologica, 2006
Large cell/anaplastic (LC/A) medulloblastoma (MB) is a recently recognized variant of medulloblastoma known to be associated with an advanced stage and a poor prognosis. Although Eberhart et al. suggested histopathologic grading of medulloblastoma in 2002, no consensus has been reached in terms of determining the criteria of an LC/A variant, and its biological behavior continues to be the subject of debate. We retrospectively analyzed 74 cases (range 0.25-15 years) of MB clinicopathologically using the criteria established by Eberhart et al. The LC/A variant was identiWed in 16 cases (22% of MB cases), Wve of which showed a poor outcome. Most LC/A variant cases revealed synaptophysin immunoexpression (75%), but no epidermal growth factor receptor (EGFR) expression. Expression of synaptophysin, NeuN, GFAP, p53, c-erbB2, and EGFR did not diVer in LC/A and non-LC/A variants. Seven of the 74 cases of medulloblastoma showed erbB2 ampliWcation by FISH, four of which were LC/A variants. N-myc ampliWcation was observed in only one LC/A variant, but no c-myc ampliWcation was found. In patients younger than 10 years, the LC/A variant showed a signiWcantly poorer outcome than the non-LC/A variant (P = 0.02), while no diVerence was found in older patients. Multivariate analysis revealed only metastasis on MRI and p53 expression, but not anaplasia as unfavorable prognostic factors. Our study suggests that prognostic implications of anaplasia in medulloblastoma are uncertain, and that the reproducibility of the histopathologic criteria of the LC/A variant should be reassessed before they can be applied in practical use.
Clinical Cancer Research, 2007
To identify better risk stratification systems in childhood medulloblastoma based on clinical factors and analysis of routinely processed formalin-fixed tumor material. Experimental Design: Formalin-fixed paraffin-embedded tumor samples from welldocumented patients treated within the prospective randomized multicenter trial HIT'91 were analyzed for DNA amplification of c-myc and N-myc (n = 133) and mRNA expression of c-myc and trkC (n = 104; compared with human cerebellum) using validated methods of quantitative PCR and reverse transcription-PCR. Results were related to clinical data and outcome. Results: TrkC and c-myc mRNA expression were identified as independent prognostic factors by multivariate analysis. Three risk groups were identified. (a) Favorable risk group: all 8 patients (2 metastatic) with high trkC (>1Â human cerebellum) and low c-myc mRNA expression (V1Â human cerebellum) remained relapse-free [7-year event-free survival (EFS), 100%]. (b) Poor risk group: 10 of 15 patients with metastatic disease and high c-myc and low trkC mRNA expression relapsed (7-year EFS, 33 %). (c) Intermediate risk group: the 7-year EFS of the remaining 78 patients was 65%. Among 47 M 0 stage patients, all 10 patients with high trkC mRNA expression remained relapse-free compared with 15 events in 37 patients with low trkC mRNA expression levels (7-year EFS, 100% versus 62%; P = 0.056). Conclusions: Whereas the collection of fresh-frozen tumor samples remains a major challenge in large clinical trials, routinely processed paraffin-embedded tissue samples can be used to quantitate the prognostic biological markers trkC and c-myc. On prospective validation of cutoff levels, this may lead to improved stratification of treatment for children with medulloblastoma.
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.
Arquivos de Neuro- …, 2003
In the past few years, the monoclonal antibody MIB-1 has been used by researchers in order to retrospectively study paraffin imbibed tumor fragments. The medulloblastoma is the most common malignant central nervous system tumor in childhood. The objectives were: determination of the mean Mib-1 LI value from these patients, as well as the prognostic value of the method.This retrospective study represents an analysis of the cellular proliferation index of posterior fossa medulloblastomas collected from 22 patients at A.C. Camargo Hospital, from January 1990 to December 1999. The histopathological diagnosis was confirmed by H&E and proliferative index (LI) was achived with Mib-1 which detects proliferating cells during G1, G2, S and M phases.The results demostrated that the mean Mib-1 was 30,1%, and ranged from 5,2% to 62,0%.In conclusion, this method has prognostic value, has to be used as routine for patients harboring medulloblastomas and the ones who have PI greater than the mean value found in this study, should be treated aggressively. KEY WORDS: medulloblastoma, labelling index (LI), MIB-1, prognostic factors. Meduloblastoma: avaliação do padrão proliferativo pelo anticorpo monoclonal Mib-1, correlação prognóstica e implicações terapêuticas PALAVRAS-CHAVE: meduloblastoma, índice proliferativo (IP), Mib1, fatores prognósticos.