Journal of Pathology and Translational Medicine

Original Articles

EGFL7 expression profile in IDH-wildtype glioblastomas is associated with poor patient outcome: Bruno Henrique Bressan da Costa, Aline Paixão Becker, Luciano Neder, Paola Gyuliane Gonçalves, Cristiane de Oliveira, Allan Dias Polverini, Carlos Afonso Clara, Gustavo Ramos Teixeira, Rui Manuel Reis, Lucas Tadeu Bidinotto; J Pathol Transl Med. 2022;56(4):205-211. Published online June 15, 2022; DOI: https://doi.org/10.4132/jptm.2022.04.22

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Background
Despite the advances in glioblastoma (GBM) treatment, the average life span of patients is 14 months. Therefore, it is urgent to identity biomarkers of prognosis, treatment response, or development of novel treatment strategies. We previously described the association of high epidermal growth factor-like domain multiple 7 (EGFL7) expression and unfavorable outcome of pilocytic astrocytoma patients. The present study aims to analyze the prognostic potential of EGFL7 in GBM isocitrate dehydrogenase (IDH)-wildtype, using immunohistochemistry and in silico approaches.
Methods
Spearman’s correlation analysis of The Cancer Genome Atlas RNA sequencing data was performed. The genes strongly correlated to EGFL7 expression were submitted to enrichment gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Additionally, EGFL7 expression was associated with patient overall survival. The expression of EGFL7 was analyzed through immunohistochemistry in 74 GBM IDH-wildtype patients’ samples, and was associated with clinicopathological data and overall survival.
Results
In silico analysis found 78 genes strongly correlated to EGFL7 expression. These genes were enriched in 40 biological processes and eight KEGG pathways, including angiogenesis/vasculogenesis, cell adhesion, and phosphoinositide 3-kinase–Akt, Notch, and Rap1 signaling pathways. The immunostaining showed high EGFL7 expression in 39 cases (52.7%). High immunolabelling was significantly associated with low Karnofsky Performance Status and poor overall survival. Cox analysis showed that GBMs IDH-wildtype with high EGFL7 expression presented a higher risk of death compared to low expression (hazard ratio, 1.645; 95% confidence interval, 1.021 to 2.650; p = .041).
Conclusions
This study gives insights regarding the genes that are correlated with EGFL7, as well as biological processes and signaling pathways, which should be further investigated in order to elucidate their role in glioblastoma biology.

Citations

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Role of EGFL7 in human cancers: A review
Cristiane de Oliveira, Paola Gyuliane Gonçalves, Lucas Tadeu Bidinotto
Journal of Cellular Physiology.2023; 238(8): 1756. CrossRef
Low EGFL7 expression is associated with high lymph node spread and invasion of lymphatic vessels in colorectal cancer
Cristiane de Oliveira, Sandra Fátima Fernandes Martins, Paola Gyuliane Gonçalves, Gabriel Augusto Limone, Adhemar Longatto-Filho, Rui Manuel Reis, Lucas Tadeu Bidinotto
Scientific Reports.2023;[Epub] CrossRef

Immunohistochemical expression of programmed death-ligand 1 and CD8 in glioblastomas: Dina Mohamed El Samman, Manal Mohamed El Mahdy, Hala Sobhy Cousha, Zeinab Abd El Rahman Kamar, Khaled Abdel Karim Mohamed, Hoda Hassan Abou Gabal; J Pathol Transl Med. 2021;55(6):388-397. Published online October 14, 2021; DOI: https://doi.org/10.4132/jptm.2021.08.04

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Abstract PDF

Background
Glioblastoma is the most aggressive primary malignant brain tumor in adults and is characterized by poor prognosis. Immune evasion occurs via programmed death-ligand 1 (PD-L1)/programmed death receptor 1 (PD-1) interaction. Some malignant tumors have responded to PD-L1/PD-1 blockade treatment strategies, and PD-L1 has been described as a potential predictive biomarker. This study discussed the expression of PD-L1 and CD8 in glioblastomas.
Methods
Thirty cases of glioblastoma were stained immunohistochemically for PD-L1 and CD8, where PD-L1 expression in glioblastoma tumor tissue above 1% is considered positive and CD-8 is expressed in tumor infiltrating lymphocytes. The expression of each marker was correlated with clinicopathologic parameters. Survival analysis was conducted to correlate progression-free survival (PFS) and overall survival (OS) with PD-L1 and CD8 expression.
Results
Diffuse/fibrillary PD-L1 was expressed in all cases (mean expression, 57.6%), whereas membranous PD-L1 was expressed in six of 30 cases. CD8-positive tumor-infiltrating lymphocytes (CD8⁺ TILs) had a median expression of 10%. PD-L1 and CD8 were positively correlated (p = .001). High PD-L1 expression was associated with worse PFS and OS (p = .026 and p = .001, respectively). Correlation of CD8⁺ TILs percentage with age, sex, tumor site, laterality, and outcomes were statistically insignificant. Multivariate analysis revealed that PD-L1 was the only independent factor that affected prognosis.
Conclusions
PD-L1 expression in patients with glioblastoma is robust; higher PD-L1 expression is associated with lower CD8+ TIL expression and worse prognosis.

Citations

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Tumor-associated microenvironment, PD-L1 expression and their relationship with immunotherapy in glioblastoma, IDH-wild type: A comprehensive review with emphasis on the implications for neuropathologists
Giuseppe Broggi, Giuseppe Angelico, Jessica Farina, Giordana Tinnirello, Valeria Barresi, Magda Zanelli, Andrea Palicelli, Francesco Certo, Giuseppe Barbagallo, Gaetano Magro, Rosario Caltabiano
Pathology - Research and Practice.2024; 254: 155144. CrossRef
Analysis of PD-L1 and CD3 Expression in Glioblastoma Patients and Correlation with Outcome: A Single Center Report
Navid Sobhani, Victoria Bouchè, Giovanni Aldegheri, Andrea Rocca, Alberto D’Angelo, Fabiola Giudici, Cristina Bottin, Carmine Antonio Donofrio, Maurizio Pinamonti, Benvenuto Ferrari, Stefano Panni, Marika Cominetti, Jahard Aliaga, Marco Ungari, Antonio Fi
Biomedicines.2023; 11(2): 311. CrossRef
Immuno-PET Imaging of Tumour PD-L1 Expression in Glioblastoma
Gitanjali Sharma, Marta C. Braga, Chiara Da Pieve, Wojciech Szopa, Tatjana Starzetz, Karl H. Plate, Wojciech Kaspera, Gabriela Kramer-Marek
Cancers.2023; 15(12): 3131. CrossRef

Prognostic role of ALK-1 and h-TERT expression in glioblastoma multiforme: correlation with ALK gene alterations: Dalia Elsers, Doaa F. Temerik, Alia M. Attia, A. Hadia, Marwa T. Hussien; J Pathol Transl Med. 2021;55(3):212-224. Published online May 11, 2021; DOI: https://doi.org/10.4132/jptm.2021.03.15

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Abstract PDF

Background
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is expressed in the developing central and peripheral nervous systems during embryogenesis. Human telomerase reverse transcriptase (h-TERT) protein resumption is the main process of preservation of telomeres that maintains DNA integrity. The present study aims to evaluate the prognostic role of ALK-1 and h-TERT protein expression and their correlation with ALK gene alterations in glioblastoma multiforme (GBM).
Methods
The current study is a retrospective study on a cohort of patients with GBM (n = 53) that attempted to detect ALK gene alterations using fluorescence in situ hybridization. ALK-1 and h-TERT proteins were evaluated using immunohistochemistry.
Results
Score 3 ALK-1 expression was significantly associated with male sex, tumor multiplicity, Ki labeling index (Ki LI), and type of therapeutic modality. Score 3 h-TERT expression exhibited a significant association with Ki LI. ALK gene amplifications (ALK-A) were significantly associated with increased Ki LI and therapeutic modalities. Score 3 ALK-1 protein expression, score 3 h-TERT protein expression, and ALK-A were associated with poor overall survival (OS) and progression-free survival (PFS). Multivariate analysis for OS revealed that ALK gene alterations were an independent prognostic factor for OS and PFS.
Conclusions
High protein expression of both ALK-1 and h-TERT, as well as ALK-A had a poor impact on the prognosis of GBM. Further studies are needed to establish the underlying mechanisms.

Citations

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Association of human telomerase reverse transcriptase promoter mutation with unfavorable prognosis in glioma: A systematic review and meta-analysis
Rongxuan Hua, Qiuxuan Li, Han Gao, Boya Wang, Chengwei He, Ying Wang, Sitian Zhang, Lei Gao, Hongwei Shang, Wen Wang, Jingdong Xu
Journal of Research in Medical Sciences.2023; 28(1): 47. CrossRef
Immunohistochemical surrogates for molecular alterations for the classification and grading of gliomas
Viharkumar Patel, Sanda Alexandrescu
Seminars in Diagnostic Pathology.2022; 39(1): 78. CrossRef
Meme Kanseri Hastalarında hTERT Gen Ekspresyonunun Klinikopatolojik Önemi
Ebubekir DİRİCAN, Burak KANKAYA, Zeynep TATAR
Sağlık Bilimlerinde Değer.2022; 12(1): 22. CrossRef
Prognostic and predictive markers in glioblastoma and ALK overexpression
Jang-Hee Kim
Journal of Pathology and Translational Medicine.2021; 55(3): 236. CrossRef

Reclassification of Mixed Oligoastrocytic Tumors Using a Genetically Integrated Diagnostic Approach: Seong-Ik Kim, Yujin Lee, Jae-Kyung Won, Chul-Kee Park, Seung Hong Choi, Sung-Hye Park; J Pathol Transl Med. 2018;52(1):28-36. Published online September 29, 2017; DOI: https://doi.org/10.4132/jptm.2017.09.25

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Abstract PDF

Background
Mixed gliomas, such as oligoastrocytomas (OA), anaplastic oligoastrocytomas, and glioblastomas (GBMs) with an oligodendroglial component (GBMO) are defined as tumors composed of a mixture of two distinct neoplastic cell types, astrocytic and oligodendroglial. Recently, mutations ATRX and TP53, and codeletion of 1p/19q are shown to be genetic hallmarks of astrocytic and oligodendroglial tumors, respectively. Subsequent molecular analyses of mixed gliomas preferred the reclassification to either oligodendroglioma or astrocytoma. This study was designed to apply genetically integrated diagnostic criteria to mixed gliomas and determine usefulness and prognostic value of new classification in Korean patients.
Methods
Fifty-eight cases of mixed OAs and GBMOs were retrieved from the pathology archives of Seoul National University Hospital from 2004 to 2015. Reclassification was performed according to genetic and immunohistochemical properties. Clinicopathological characteristics of each subgroup were evaluated. Overall survival was assessed and compared between subgroups.
Results
We could reclassify all mixed OAs and GBMOs into either astrocytic or oligodendroglial tumors. Notably, 29 GBMOs could be reclassified into 11 cases of GBM, IDH-mutant, 16 cases of GBM, IDH-wildtype, and two cases of anaplastic oligodendroglioma, IDH mutant. Overall survival was significantly different among these new groups (p<.001). Overall survival and progression-free survival were statistically better in gliomas with IDH mutation, ATRX mutation, no microscopic necrosis, and young patient age (cut off, 45 years old).
Conclusions
Our results strongly suggest that a genetically integrated diagnosis of glioma better reflects prognosis than former morphology-based methods.

Citations

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The prognostic significance of p16 expression pattern in diffuse gliomas
Jin Woo Park, Jeongwan Kang, Ka Young Lim, Hyunhee Kim, Seong-Ik Kim, Jae Kyung Won, Chul-Kee Park, Sung-Hye Park
Journal of Pathology and Translational Medicine.2021; 55(2): 102. CrossRef
Dynamic susceptibility contrast and diffusion MR imaging identify oligodendroglioma as defined by the 2016 WHO classification for brain tumors: histogram analysis approach
Anna Latysheva, Kyrre Eeg Emblem, Petter Brandal, Einar Osland Vik-Mo, Jens Pahnke, Kjetil Røysland, John K. Hald, Andrés Server
Neuroradiology.2019; 61(5): 545. CrossRef

PD-L1 Expression and Combined Status of PD-L1/PD-1–Positive Tumor Infiltrating Mononuclear Cell Density Predict Prognosis in Glioblastoma Patients: Jiheun Han, Yongkil Hong, Youn Soo Lee; J Pathol Transl Med. 2017;51(1):40-48. Published online December 15, 2016; DOI: https://doi.org/10.4132/jptm.2016.08.31

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Abstract PDF

Background
Programmed death ligand 1 (PD-L1) in tumor cells is known to promote immune escape of cancer by interacting with programmed cell death 1 (PD-1) in tumor infiltrating immune cells. Immunotherapy targeting these molecules is emerging as a new strategy for the treatment of glioblastoma (GBM). Understanding the relationship between the PD-L1/PD-1 axis and prognosis in GBM patients may be helpful to predict the effects of immunotherapy.
Methods
PD-L1 expression and PD-1–positive tumor infiltrating mononuclear cell (PD-1+tumor infiltrating mononuclear cell [TIMC]) density were evaluated using tissue microarray containing 54 GBM cases by immunohistochemical analysis; the associations with patient clinical outcomes were evaluated.
Results
PD-L1 expression and high PD-1+TIMC density were observed in 31.5% and 50% of GBM cases, respectively. High expression of PD-L1 in tumor cells was an independent and significant predictive factor for worse overall survival (OS; hazard ratio, 4.958; p = .007) but was not a significant factor in disease-free survival (DFS). PD-1+TIMC density was not correlated with OS or DFS. When patients were classified based on PD-1 expression and PD-1+TIMC density, patients with PD-L1+/PD-1+TIMC low status had the shortest OS (13 months, p = .009) and DFS (7 months, p = .053).
Conclusions
PD-L1 expression in GBM was an independent prognostic factor for poor OS. In addition, combined status of PD-L1 expression and PD-1+TIMC density also predicted patient outcomes, suggesting that the therapeutic role of the PD-1/PD-L1 axis should be considered in the context of GBM immunity.

Citations

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Immunohistochemical Classification of Primary and Secondary Glioblastomas: Kyu Sang Lee, Gheeyoung Choe, Kyung Han Nam, An Na Seo, Sumi Yun, Kyung Ju Kim, Hwa Jin Cho, Sung Hye Park; Korean J Pathol. 2013;47(6):541-548. Published online December 24, 2013; DOI: https://doi.org/10.4132/KoreanJPathol.2013.47.6.541

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Abstract PDF

Background

Glioblastomas may develop de novo (primary glioblastomas, P-GBLs) or through progression from lower-grade astrocytomas (secondary glioblastomas, S-GBLs). The aim of this study was to compare the immunohistochemical classification of glioblastomas with clinically determined P-GBLs and S-GBLs to identify the best combination of antibodies for immunohistochemical classification.

Methods

We evaluated the immunohistochemical expression of epidermal growth factor receptor (EGFR), p53, and isocitrate dehydrogenase 1 (IDH-1) in 150 glioblastoma cases.

Results

According to clinical history, the glioblastomas analyzed in this study consisted of 146 P-GBLs and 4 S-GBLs. Immunohistochemical expression of EGFR, p53, and IDH-1 was observed in 62.6%, 49.3%, and 11.1%, respectively. Immunohistochemical profiles of EGFR(+)/p53(-), IDH-1(-)/EGFR(+)/p53(-), and EGFR(-)/p53(+) were noted in 41.3%, 40.2%, and 28.7%, respectively. Expression of IDH-1 and EGFR(-)/p53(+) was positively correlated with young age. The typical immunohistochemical features of S-GBLs comprised IDH-1(+)/EGFR(-)/p53(+), and were noted in 3.6% of clinically P-GBLs. The combination of IDH-1(-) or EGFR(+) was the best set of immunohistochemical stains for identifying P-GBLs, whereas the combination of IDH-1(+) and EGFR(-) was best for identifying S-GBLs.

Conclusions

We recommend a combination of IDH-1 and EGFR for immunohistochemical classification of glioblastomas. We expect our results to be useful for determining treatment strategies for glioblastoma patients.

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Clinical, immunohistochemical, and molecular genetic prognostic factors in adult patients with glioblastoma
N. V. Lobanova, L. V. Shishkina, M. V. Ryzhova, G. L. Kobyakov, R. V. Sycheva, S. A. Burov, A. V. Lukyanov, Zh. R. Omarova
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A Consideration of MGMT Gene Promotor Methylation Analysis for Glioblastoma Using Methylation-Specific Polymerase Chain Reaction and Pyrosequencing.: Sang Hwa Lee, Tae Sook Hwang, Young Cho Koh, Wook Youn Kim, Hye Seung Han, Wan Seop Kim, Young Sin Ko, So Dug Lim; Korean J Pathol. 2011;45(1):21-29.; DOI: https://doi.org/10.4132/KoreanJPathol.2011.45.1.21

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Abstract PDF

BACKGROUND
O6-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation is currently the most promising predictive marker for the outcome and benefit from temozolomide treatment in patients with glioblastoma, but there is no consensus on the analysis method for assessing the methylation status in the molecular diagnostic field. The objective of this study was to evaluate methylation-specific polymerase chain reaction (MSP) and pyrosequencing methods for assessing MGMT gene promotor methylation of glioblastoma as well as assessing the MGMT protein expression by immunohistochemistry.
METHODS
Twenty-seven cases of glioblastoma from the archives at the Department of Pathology Konkuk University Hospital were selected. MGMT promoter methylation was evaluated by MSP and the pyrosequencing methods. The MGMT expression was also measured at the protein level by immunohistochemistry.
RESULTS
Overall, MGMT hypermethylation was observed in 44.4% (12/27 cases) of the case of glioblastoma using either MSP or pyrosequencing. The concordant rate was 70.3% (19/27 cases) between MSP and pyrosequencing for MGMT methylation. There was no correlation between MGMT methylation and the protein expression. No significant differences in progression free survival and overall survival were seen between the methylated group and the unmethylated group by using either MSP or pyrosequencing. The status of the MGMT protein expression was correlated with progression free survival (p=0.026).
CONCLUSIONS
In this study the concordance rate between MSP and the pyrosequencing methods for assessing MGMT gene promotor methylation was relatively low for the cases of glioblastoma. This suggests that more reliable techniques for routine MGMT methylation study of glioblastoma remain to be developed because of quality control and assurance issues.

Citations

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Prognostic Role of Methylation Status of theMGMTPromoter Determined Quantitatively by Pyrosequencing in Glioblastoma Patients
Dae Cheol Kim, Ki Uk Kim, Young Zoon Kim
Journal of Korean Neurosurgical Society.2016; 59(1): 26. CrossRef
Distinct genetic alterations in pediatric glioblastomas
Sun-ju Byeon, Jae Kyung Myung, Se Hoon Kim, Seung-Ki Kim, Ji Hoon Phi, Sung-Hye Park
Child's Nervous System.2012; 28(7): 1025. CrossRef
MGMTGene Promoter Methylation Analysis by Pyrosequencing of Brain Tumour
Young Zoon Kim, Young Jin Song, Ki Uk Kim, Dae Cheol Kim
The Korean Journal of Pathology.2011; 45(5): 455. CrossRef

Angiogenensis and Overexpression of p53 Gene Produc in Brain Tumor.: Jeong Yun Shim, Ho Guen Kim, Tai Seung Kim; Korean J Pathol. 1997;31(1):23-33.

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Abstract PDF: Angiogenesis depends on the net balance between positive and negative angiogenic factors. Tumor cells are angiogenic resulting from increased production of positive factors and decreased production of negative factors. Among these, vascular endothelial growth factor and glioma- derived angiogenesis inhibiting factor are related to glioblastoma multiforme. The p53 gene is more frequently mutated than any other known oncogene or tumor suppressor gene in human tumors including glioblastoma multiforme. Angiogenesis is reported to be controlled by p53 regulation in recent studies. To examine the effect of p53 overexpression on angiogenesis in glioblastoma multiforme, we performed immunohistochemical staining in 51 cases of glioblastoma multiforme, using monoclonal antibodies to p53 protein and factor VIII. 20 cases of low grade astrocytoma were used as control. p53 overexpression was present in 15(75%) of 20 cases of low grade astrocytoma and the mean vessel count was 37.7+/-9.9 at x200 field and 17.5+/-5.8 at x400 field. p53 overexpression was present in 35(68%) of 51 cases of glioblastoma multiforme and the mean vessel count was 91.9 45.8 at x200 field and 40.7 19.1 at x400 field. Mean vessel count in low grade astrocytoma with p53 overexpression was 39.4 10.2 at x200 field and 18.9 5.7 at x400 field, while in cases without p53 overexpression it was 32.4+/-7.6 at x200 field and 13.2 3.5 at x400 field. Mean vessel count in glioblastoma multiforme with p53 overexpression was 94.5+/-51.8 at x200 field and 42.1+/-16.8 at x400 field, while in cases without p53 overexpression it was 86.1+/-29.5 at x200 field and 37.1+/-16.8 at x400 field. The mean survival time was 12.4 months in the 39 cases of glioblastoma multiforme in which follow-up studies were possible. Significant prognostic factors were age, p53 overexpression and adjuvant therapy. These results show that p53 gene mutation is one of the many contributing factors to angiogenesis in glioblastoma multiforme. In addition, other oncogenes and tumor suppressor genes, as well as growth factors may be involved. Age, p53 overexpression and adjuvant therapy proved to be significant prognostic factors, while microvessel density was not.

Molecular Subtypes of Primary Glioblastoma Identified by Gene Expression Profiling.: Ghee Young Choe, S Mischel Paul; Korean J Pathol. 2002;36(5):328-337.

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Abstract PDF: BACKGROUND
The over-expression of the epidermal growth factor receptor (EGFR) occurs in nearly 50% of primary glioblastoma multiforme (GBM). Disruption of multiple signaling pathways is a critical factor in regulating the biological and clinical behavior of GBMs. In the future, therapy that specifically targets these disrupted pathways may represent the best potential treatment for patients with GBM. Large scale gene expression profiling provides a powerful approach to identify these disrupted genetic pathways and to uncover previously unknown molecular subtypes.
METHODS
We used 13 cases of primary GBM biopsy samples obtained from untreated patients and Affymetrix high-density oligonucleotide arrays to identify novel subsets of primary GBMs.
RESULTS
We showed that the expression of 90 genes differentiate EGFR+ from EGFR non-expressing (EGFR-) de novo GBMs, including expression of a number of potentially targetable molecules that act as growth/survival factors for GBMs. We also demonstrated the presence of two additional molecular subtypes of primary GBMs, including one characterized by the coordinate upregulation of contiguous genes on chromosome 12q13-15, which has a distinct global gene expression profile and expresses both astrocytic and oligodendroglial genes.
CONCLUSION
We have shown that there are EGFR+ primary GBMs, GBMs with coordinate upregulation of genes on chromosome 12q13-15, and primary GBMs lacking either alteration. Moreover, they have distinct transcriptional profiles. Our findings strongly suggest that the three GBMs are biologically different tumor types, despite their identical microscopic appearance, and provide an important first step in developing a molecular taxonomy of GBMs.

Alterations of 9p21-22 Region Encoding Genes in Primary Glioblastomas.: Hong Jik Doh, Seong Il Suh, Dong Won Kim, Il Man Kim, Man Bin Yim, Eun Ik Son, Kun Young Kwon, Sang Sook Lee, Sang Pyo Kim; Korean J Pathol. 2002;36(6):394-399.

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Abstract PDF: BACKGROUND
Glioblastomas are one of the most common and aggressive malignant glial tumors occuring in the central nervous system. This study analyzed the status of p15INK4b, p14ARF, p16INK4a, MTAP, IFNA, and IFNB genes in 36 primary glioblastomas to investigate whether the inactivation of these genes participate in primary glioblastoma tumorigenesis.
METHODS
We used polymerase chain reaction, polymerase chain reaction/single strand conformational polymorphism (PCR/SSCP) analysis, and methylation-specific PCR.
RESULTS
Homozygous deletions at the p16INK4a gene were detected in 11 cases (30.5%) of 36 primary glioblastomas, and the promoter hypermethylation was found in 3 cases (8.3%) of 36 primary glioblastomas. In mutational analysis for the p16INK4a gene by PCR/SSCP, there was no abnormal mobility-shifted band in 36 cases of primary glioblastomas. The overall frequency of p16INK4a alterations including homozygous deletion and promoter hypermethylation in 36 primary glioblastomas was 38.8% (14 of 36). Deletions of p15INK4b were noted in 4 cases (11.1%), whereas deletions of the p14ARF and MTAP genes were detected in 1 case of 36 cases of primary glioblastomas. But deletions of the INFA and B genes were not found.
CONCLUSIONS
These results suggest that alterations of the p16INK4a gene can be important mechanisms of the tumorigenesis of primary glioblastomas, and the p16INK4a gene is inactivated by mechanisms including homozygous deletion and promoter hypermethylation.

Case Reports

Congenital Desmoplastic Cerebral Glioblastoma: A Case Report.: Hong Il Ha, Seung Mo Hong, Seung Koo Lee, Shin Kwang Khang; Korean J Pathol. 2002;36(6):440-444.

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Abstract PDF: Desmoplastic cerebral glioblastoma has been described recently and is a very rare histologic variant of glioblastoma. We report a case of congenital cerebral glioblastoma associated with intense desmoplastic stromal reaction. A male infant was born at 36 gestational weeks by Cesarian section. He had a brain tumor, which was detected by fetal ultrasonography. The tumor was partially resected 2 months after the day of the boy's birth and totally resected when he was one year old. The microscopic features of the tumor were those of glioblastoma, including high cellularity, frequent mitotic figures, vascular endothelial proliferation, and geographic palisading necrosis. The tumor showed an area of intense desmoplasia where tumor cells were surrounded by dense reticulin fibers. The desmoplastic cerebral tumors in children may be a distinct group of brain tumor, and it is important to understand the entity of these tumors which generally seem to be associated with more favorable prognosis compared to other high grade brain tumors.

Primary Leptomeningeal Glioblastomatosis Detected in Cerebrospinal Fluid Cytology: A Case Report.: Ki Seok Jang, Si Hyong Jang, Young Soo Song, Moon Hyang Park; Korean J Cytopathol. 2005;16(2):110-114.

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Abstract PDF: Primary leptomeningeal glioblastomatosis is a rare and fatal tumor of the central nervous system, the condition is characterized by diffuse infiltration of the tumor in the meninges without evidence of primary tumor within the brain or spinal cord. We reported an unusual case of leptomengial glioblastomatosis, which was detected by the consecutive cerebrospinal fluid (CSF) cytology with application of immunohistochemistry, in addition to its cytologic findings. A healthy 21 year old man, who was enlisted in the army, presented with a stuporous mental state and diffuse enhancement of meninges without evidence of primary mass lesion in the brain and spinal cord on magnetic resonance imaging(MRI). CSF cytology showed small loose clusters of tumor cells with single cells and lymphocytes. The tumor showed variable pleomorphism with coarse chromatin, irregular nuclear membranes and multi lobated nuclei. On immunohistochemical staining, the tumor cells were founded to be positive for GFAP. In conjunction with radiologic findings, brain biopsy confirmed the diagnosis of leptomenigeal glioblastomatosis. The use of immunohistochemistry is helpful in confirming CSF cytologic diagnosis in patients with primary leptomeningeal glioblastomatosis.

Original Articles

Overexpression of Mutant p53 in Human Anaplastic Astrocytoma and Glioblastoma Multiforme.: Sang Sook Lee, Kam Rae Cho, Cheoul Hee Yun, Sang Pyo Kim, Kwan Kyu Park, Eun Sook Chang, Eun Ik Sohn; Korean J Pathol. 1994;28(4):376-380.

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Abstract PDF: A total of 30 cases of cerebral gliomas, including 6 cases of low grade astrocytomas, 6 anaplasticastrocytoomas and l8 glioblastomas multiforme, was examined immunohistochemically to demonstrate the overexpression of mutant forms of p53 protein and to evaluate their relationships with histological subtypes. A p53 monoclonal antibody was applied to the routine formalin fixed, paraffin-embedded tissues for this study using microwave-assisted avidin-biotin method. Overexpression of p53 protein was identified in 4 out of 6 anaplastic astrocytomas (66.7%) and in l3 out of l8 glioblastomas multiforme (72.2%). No immunohistochemical positivity of p53 was found in adjacent normal brain tissue, gliosis and 6 cases of astrocytoma. These results suggest that overexpression of mutant p53 may be an important step in the development and progression of malignant astrocytoma, especially of the aggressive subtypes of glioma, including glioblastoma multiforme.

Histologic Grading of Astrocytic Neoplasms in Conjunction with Evaluation of Proliferative Activity Using Ag-NORs Count PCNA Expression, and Flow CYtometric DNA Analysis.: Mee Yon Cho, Soon Hee Jung, Tal Seung Kim, Yong Pyo Han; Korean J Pathol. 1994;28(1):49-55.

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Abstract PDF: Although the histologic grade of astrocytic neoplasms of the brain have been used as a prognostic factor, the lack of an objective criteria is possible to create the disagreement of classification. We evaluated 25 cases of astrocytic neoplasms of brain to document the usefulness of prolifera-tive potential of tumor as a prognostic indicator and the correlation with histologic grade by Nils Ringertz. The Ringertz's classification was relatively simple in an application among the variable systems and easy to define the differentiate from grade to grade. The examined cases were com-prised of 7 astrocytomas, 9 anaplastic astrocytomas and 9 glioblastoma multif6rmes. The prolife-rative potential of tumors were measured by Ag-NORs count, PCNA labeling index and flow cytometric analysis. The mean numbers of Ag-NORs per cell and PCNA labeling index were sig-nificantly differ among each histologic grade. In addition, abnormal DNA content and high prolif-erative index were frequently identified in anaplastic astrocytoma and glioblastoma multiforme. Therefore, the Ag-NORs counts, PCNA labeling index, DNA index and proliferative index were well correlated with the histologic grade.

Case Report

Giant Cell Glioblastoma: A report of two cases.: Seoung Hyp Park, Kap No Lee, Seung Yong Paik; Korean J Pathol. 1988;22(1):110-117.

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Abstract PDF: A rare variant of glioblastoma characterized by giant or monster cells is now well recognized. However, this tumor had been remained in controversy on its pathogenesis, and the tumor had been considered to be a sarcoma until 1968, when the electronemicroscopic study demonstrated the presence of filaments mesuring 80 in diameter in the perikarya in giant cells as well as in smaller, better differentiated cells. The peroxidase antiperoxidase stain of glial fibrillary acid protein shows positive glial fibrillary fibers in their cytoplasm, accordingly the giant cells has been recognized as being of astrocytic origin. This concept has been redocumented by light microscopy since PTAH-positive astrocytic fibers are present in large numbers of neoplastic cells. The two cases reported here were frontal and occipital giant cell glioblastomas in 58 years old male and 44 years old women, respectively. On light microscopy, the tumor showed numberous characteristic giant or monster cells as well as the same features seen in the usual glioblastoma. The electron microscopy and special stains, PTAH and GFAP confirmed that the giant cells were in glial origin.

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