Morphophenotype of medulloblastoma in children and adults. The size of nuclei.
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OBJECTIVE Uniform cells with round, regular nuclei characterize the typical histologic aspect of medulloblastoma. Enlargement of nuclei distinguishes the large-cell medulloblastoma variant and is associated with a poor prognosis in pediatric medulloblastomas. The aim of the present study was to compare the size of nuclei between pediatric and adult medulloblastomas by a morphometric analysis. MATERIAL AND METHODS In 79 neurosurgical specimens of cerebellar medulloblastomas, the maximum nuclear diameter of the largest nuclei was measured. Measurements were performed with a digital-image analysis system. The measure of the maximum diameter was chosen in order to reduce the split cell error. RESULTS The difference between the mean values in children and adults was statistically significant (p = 0,001). The distribution of maximum values measured in each case had two distinct peaks in the two age groups, in 3.5% of adult cases and in more than 30% of pediatric cases the maximum nuclear size was superior to 12 microm. CONCLUSIONS The present results show that nuclei of tumor cells in pediatric medulloblastomas are larger than those in adult medulloblastomas and confirm that the phenotype of medulloblastoma is different in the two age groups. Distinct genetic events can, thus, underlie medulloblastoma in childhood and adult age, the prognostic role of genetic variables can differ by age.Keywords:
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Osteosarcoma is the most frequent primary malignant bone tumor. Distinct histological features are distinguishable based on the morphology of the tumor. Differences in nuclei size and shape are often observed in osteosarcoma reflecting its broad histopathological heterogeneity. This study explores the relevance of two nuclear parameters in osteosarcoma: large area and round shape. Computerized nuclear morphometry was performed in 56 conventional osteosarcoma preoperative biopsies. The mean patient follow-up time was 35.1 months. Based on the nuclear area, no significant difference (P = 0.09) in overall survival between patients with large (> 42.5 μm(2)) and small (< 42.5 μm(2)) tumor nuclei was found. However, when cases with large and round nuclei were analyzed jointly (> 42.5 μm(2) and coefficient of nuclear roundness > 0.7), these two parameters together were likely to be a predictive factor (P = 0.05). Osteosarcoma patients with large and round tumor nuclei had a better outcome than patients with small and polymorphic (ovoid or spindle-shaped) nuclei. In this study, nuclear morphometry proved to be a useful tool to shed light on the biology of osteosarcoma showing that some morphometric parameters can be easily applied to help identifying patients with a good prognosis.
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✓ The deoxyribonucleic acid (DNA) content of 53 medulloblastomas was analyzed by means of flow cytometry and compared with the clinical and histological findings in the host patients. Analysis of DNA showed that about half of the tumors were diploid and the other half were aneuploid. More diploid tumors were found among patients of a young age, but the difference was without statistical significance. Cellular differentiation of the tumor did not correlate with DNA ploidy. No correlation was found between Chang's T staging system and the DNA ploidy, whereas the M staging correlated with the ploidy; diploid medulloblastomas had a greater tendency to metastasize than aneuploid medulloblastomas (p = 0.0003). Four-year survival was compared with the extent of resection and DNA ploidy. The patients with total resection and aneuploid medulloblastoma had a better prognosis than those with subtotal resection and diploid tumor (p = 0.001). There was only one survivor among eight patients with subtotally resected diploid medulloblastomas, while all of the seven patients with totally resected aneuploid medulloblastomas survived. Comparison of the G 0 /G 1 phase fraction and S phase fraction in the surviving group and the deceased group offered no significant information.
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Classical and desmoplastic medulloblastomas (MBs) have been suspected to be biologically different, though comparative studies on markers of biological aggressiveness in these two variants are sparse in the literature. 87 classical and 43 desmoplastic variants of MB were studied with respect to clinical and histological characteristics, MIB-1 labeling index (MIB-1 LI), apoptotic index (AI), ratio of AI to MIB-1 LI, expression of p53 and Bcl-2 protein and 3-year progression-free survival. The only differences documented between the variants were with regard to age distribution and location. Thus, classical histology cases occurred predominantly in children and 80% were midline in location. In contrast, lateral location was seen more frequently with tumors of desmoplastic histology, which occurred in an almost equal distribution between children (56%) and adults (44%). No difference was noted between the variants with regard to proliferation index, apoptotic index, their ratio on or their molecular controls (p53 and Bcl-2). This was reflected in the clinical outcome wherein no significant difference was observed in the 3-year progression-free survival between the variants. It is concluded that the two histological variants of medulloblastoma are not different with regard to biological parameters of aggressiveness. The growth rate and clinical outcome in medulloblastomas have no correlation with the histological variant.
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Proliferation index
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Thirty-one surgically excised glioblastomas multiforme (GBM) and 34 intracranial metastatic carcinomas were studied morphometrically to determine the confidence with which these two common lesions can be distinguished on the basis of their nuclear sizes and shapes. Planimetry was used to characterize the nuclei in these lesions and two primary variables were calculated: (1) the mean nuclear size and (2) a measure of roundness, the mean 'form PE'. The two neoplasms were then compared by logistic regression which calculated the coefficients of two equations expressing the probability that each of the 65 lesions was a GBM. There were significant differences between the two lesions (p = 0.001 or less) in both nuclear size and shape. The nuclei of the GBM were smaller and less round. The first logistic regression equation utilized mean nuclear size and mean form PE and 'correctly' classified 26 of the GBM and 30 of the carcinomas. The second equation utilized mean nuclear area and the coefficient of variation of nuclear area. Only 6 neoplasms, 3 metastatic carcinomas and 3 GBM, were 'incorrectly' classified. The results suggest that there are significant differences in nuclear size and shape in these two lesions and that these differences are amenable to morphometric and statistical study. Similar predictive equations should be tested as potential diagnostic aids.
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Abstract Bromodeoxyuridine (BrdU), 150 to 200 mg/m2, was administered at the time of operation to 20 pediatric patients with neuroectodermal tumors to label tumor cells in the S phase. Immunocytochemical techniques were used on excised tumor specimens to detect cells containing BrdU, and the BrdU labeling index (LI) was calculated as the number of BrdU-labeled cells divided by the total number of cells counted. Four medulloblastomas, three glioblastomas multiforme, and two highly anaplastic astrocytomas had average BrdU LIs of 13.0 ± 3.0% (SE), 12.7 ± 4.3%, and 14.6 ± 6.7%, respectively. Three of nine moderately anaplastic astrocytomas had BrdU LIs of greater than 1% (average, 6.5 ± 2.4%), whereas six had LIs of less than 1%. In two juvenile pilocytic astrocytomas, which are considered slow-growing, the BrdU LIs were unexpectedly high, averaging 6.5 ± 1.4%. Thus, pediatric medulloblastomas, glioblastomas multiforme, highly anaplastic astrocytomas, and a minority of moderately anaplastic astrocytomas had high proliferative potentials, whereas most of the moderately anaplastic astrocytomas had low proliferative potentials. Although the number of cases in this study is still too small to yield statistically significant comparisons, the results indicate that some pediatric tumors have considerably higher LIs than histologically similar adult tumors studied previously.
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Anaplastic astrocytoma
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Aims : To determine whether nuclear morphometry can be used in pretreatment diagnostic procedures to guide the therapy of childhood rhabdomyosarcoma (RMS). Materials and methods : Biopsy specimens obtained from 108 patients with rhabdomyosarcoma aged between 1 and 217 months treated in 12 paediatric oncology departments in Poland were evaluated. There were 65 (60.2%) specimens of embryonal rhabdomyosarcoma (RME), 32 (29.6%) of alveolar RMS (RMA) and 11 (10.2%) cases of undifferentiated RMS (RMU). The clinical data from all analysed patients were evaluated. Nuclear morphometry was performed semiautomatically on haematoxylin–eosin‐stained sections using the MultiScan v.8.08 Computer Scanning System and an Olympus BX 50 microscope with a × 40 magnification lens. Results : In the RMA subtype cells with spindle‐shape nuclei were less common ( P = 0.013) and cell nuclei were generally more round in comparison with RME ( P = 0.033). The clinical outcome was better if the nuclei seen in biopsies of RMS were more spindle‐shaped (event‐free survival 0.51 and 0.23, respectively; P = 0.04) or more cells with spindle‐shaped nuclei were observed (event‐free survival 0.5 and 0.28, P =0.035). RME patients with small nuclei had a better outcome then patients with large nuclei ( P = 0.014). In the RMA/RMU group, patients with small tumour cell nuclei had a worse prognosis than patients with larg tumour cell nuclei ( P = 0.046). Conclusions : Nuclear morphometry is a useful tool in the assessment of children with RMS. Additionally, certain morphometric parameters could be easily applied in a selection of patients with good prognosis.
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Alveolar rhabdomyosarcoma
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Cell cycle analysis by flow cytometry has not been adequately studied in pediatric brain tumors. We investigated the value of a modified rapid (within 6 min) cell cycle analysis protocol for the characterization of malignancy of pediatric brain tumors and for the differentiation of neoplastic from nonneoplastic tissue for possible intraoperative application. We retrospectively studied brain tumor specimens from patients treated at our institute over a 5-year period. All tumor samples were histopathologically verified before flow-cytometric analysis. The histopathological examination of permanent tissue sections was the gold standard. There were 68 brain tumor cases. All tumors had significantly lower G0/G1 and significantly higher S phase and mitosis fractions than normal brain tissue. Furthermore low-grade tumors could be differentiated from high-grade tumors. DNA aneuploidy was detected in 35 tumors. A correlation between S phase fraction and Ki-67 index was found in medulloblastomas and anaplastic ependymomas. Rapid cell cycle analysis by flow cytometry is a promising method for the identification of neoplastic tissue intraoperatively. Low-grade tumors could be differentiated from high-grade tumors. Thus, cell cycle analysis can be a valuable adjunct to the histopathological evaluation of pediatric brain tumors, whereas its intraoperative application warrants further investigation.
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To show any possible correlation of some karyometric variables with tumor size in patients with brain astrocytoma, in order to confirm karyometry as an objective histological method.The study included 63 patients of different ages and both genders with brain astrocytoma histologically confirmed on the surgically removed material. In all patients maximal tumor excision was done, and all were postoperatively treated according to different therapeutic protocols. Tumor size (preoperative CT scan) was correlated with the duration of survival and the values of some karyometric tumor variables: area, density, maximal axis, mean axis, minimal axis, circumference, roundness, integrated optical density (IOD) and number of nuclei.Patients were separated into 3 groups according to the average tumor diameter. There were 34 cases of medium-sized tumors, 12 of small and 17 of large-sized tumors, and their respective survival was 83, 97 and 24 weeks. Patients with large tumors had statistically shorter survival compared to those with medium and small tumors (log-rank test, p=0.0122). Seven out of 9 examined karyometric variables were significantly related (p<0.05) to the tumor size: area, maximal axis, mean axis, minimal axis, circumference, roundness and IOD.Patients with larger tumors have shorter survival. The results of our morphometric analysis of the tumor cell nuclei, after correlation with CT findings, revealed that nuclear pleomorphism and larger nuclear size are associated with larger brain astrocytomas.
Pleomorphism (cytology)
Brain tumor
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Objective: To provide histopathological subtypes of medulloblastomas (according to 2007 WHO Classification of tumors of the central nervous system) that were previously diagnosed during 1998 to 2005 in Siriraj Hospital, and to characterize the immunophenotypic patterns of medulloblastomas in correlation with these subtypes. Methods: All diagnosed medulloblastomas collected during 1998 to 2005 in the Department of Pathology, Siriraj Hospital were reviewed and classified according to WHO classification (2007) by H&E staining. Furthermore, we performed immunohistochemical studies, including synaptophysin, glial fibrillary acidic protein (GFAP), neurofilament, and Ki-67 to characterize the immunophenotypical patterns of medulloblastoma correlated with morphological variants. Statistic analyses were Tukey HSD, Mann-Whitney test, and Fisher’s exact test. Results: Of 41 medulloblastomas, 32 cases were classic type (78.05%), 6 cases were large cell/anaplastic variant (14.63%), and 3 cases were desmoplastic variant (7.32%). This study showed significantly increased Ki-67 indices in the large cell/ anaplastic variant compared to either classic medulloblastoma or desmoplastic/nodular variant (p <0.05). There is no statistical difference in immunophenotypes of synaptophysin, GFAP, or neurofilament between each subtype. Conclusion: According to 2007 WHO classification of tumor of the central nervous system 2007, in our study, the majority was medulloblastoma classic type, followed by large cell/anaplastic and desmoplastic/nodular variants, respectively. Statistical significance of Ki-67 indices suggests its applicable adjuvant diagnostic tool to distinguish the large cell/anaplastic variant from others. Objective: To provide histopathological subtypes of medulloblastomas (according to 2007 WHO Classification of tumors of the central nervous system) that were previously diagnosed during 1998 to 2005 in Siriraj Hospital, and to characterize the immunophenotypic patterns of medulloblastomas in correlation with these subtypes. Methods: All diagnosed medulloblastomas collected during 1998 to 2005 in the Department of Pathology, Siriraj Hospital were reviewed and classified according to WHO classification (2007) by H&E staining. Furthermore, we performed immunohistochemical studies, including synaptophysin, glial fibrillary acidic protein (GFAP), neurofilament, and Ki-67 to characterize the immunophenotypical patterns of medulloblastoma correlated with morphological variants. Statistic analyses were Tukey HSD, Mann-Whitney test, and Fisher’s exact test. Results: Of 41 medulloblastomas, 32 cases were classic type (78.05%), 6 cases were large cell/anaplastic variant (14.63%), and 3 cases were desmoplastic variant (7.32%). This study showed significantly increased Ki-67 indices in the large cell/ anaplastic variant compared to either classic medulloblastoma or desmoplastic/nodular variant (p <0.05). There is no statistical difference in immunophenotypes of synaptophysin, GFAP, or neurofilament between each subtype. Conclusion: According to 2007 WHO classification of tumor of the central nervous system 2007, in our study, the majority was medulloblastoma classic type, followed by large cell/anaplastic and desmoplastic/nodular variants, respectively. Statistical significance of Ki-67 indices suggests its applicable adjuvant diagnostic tool to distinguish the large cell/anaplastic variant from others.
Synaptophysin
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