|Year : 2020 | Volume
| Issue : 1 | Page : 13-15
CD34 neural progenitor cells in glioblastoma multiforme
Reneta Georgieva1, Emran Lyutfi1, George S Stoyanov2, Deyan Dzhenkov2
1 Forensic Medicine and Deontology, Faculty of Medicine, Medical University – Varna “Prof. Dr. Paraskev Stoyanov,” Varna, Bulgaria
2 Department of General and Clinical Pathology, Forensic Medicine and Deontology, Faculty of Medicine, Medical University – Varna “Prof. Dr. Paraskev Stoyanov”, Varna, Bulgaria
|Date of Submission||24-Dec-2019|
|Date of Acceptance||20-Jan-2020|
|Date of Web Publication||13-Apr-2020|
Dr. George S Stoyanov
Hr. Smirnenski 1 Blvd, Varna 9000
Source of Support: None, Conflict of Interest: None
Background and Aim: Glioblastoma multiforme (GBM) is a World Health Organization (WHO) Grade IV malignant tumor with astrocytic differentiation. Despite medical advances over the past few decades, the life expectancy of patients with GBM has remained relatively unchanged 8–12 months. There are two proposed mechanisms for the development of GBM – a natural progression of lower WHO-grade astrocytoma and de novo development. Both theories, however, center on neural progenitor cells in the central nervous system. The aim of this study was to evaluate the significance of CD34 neural stem cell progenitors in GBM. Materials and Methods: Fourteen cases (eight males and seven females, age 16–74 years) of tumors with astrocytic differentiation were evaluated using the automated immunohistochemistry detection algorithm of Qupath v0.2.0-m4. Due to CD34 marking not only neural progenitors but also endothelial cells, the tumors were evaluated over an area of 76 mm, with blood vessels excluded from the analysis. In superficial tumors, again, an area of 76 mm was evaluated in the subpial one. This study was approved by the Committee on Ethics for Scientific Research, Medical University – Varna “Prof. Dr. Paraskev Stoyanov” (protocol no. 20) on April 26, 2012. Results: The tumors included 11 GBMs, 2 gliosarcomas, and 1 WHO Grade II astrocytoma. Only the GBMs were subjected to statistical analysis due to the small sample size. Both the hotspot (P = 0.076) and subpial (P = 0.243) values did not show a correlation with patients' survival, with borderline expression being defined as >3.6% (high) and <3.6% (low). Conclusion: Despite the specific patterns of growth and diffuse spread of CD34+ progenitors, their percentage does not correlate with patients' survival.
Keywords: Cancer stem cells, CD34, cell aggregation, glioblastoma, neural stem cell progenitors, stem cell, survival
|How to cite this article:|
Georgieva R, Lyutfi E, Stoyanov GS, Dzhenkov D. CD34 neural progenitor cells in glioblastoma multiforme. Glioma 2020;3:13-5
| Introduction|| |
Glioblastoma multiforme (GBM) is a World Health Organization (WHO) Grade IV malignant tumor with astrocytic differentiation. The two mechanisms proposed for the development of GBM are a natural progression from low-grade astrocytoma and de novo development. Both, however, define neural progenitor cells in the central nervous system and the activation of neoplastic genes within them as the key in the pathogenesis. One such population of cells within the central nervous system is the CD34 neural progenitors.
This study aimed to evaluate the presence, distribution, and prognostic role of CD34 progenitor cells in GBM and other WHO-grade tumors with astrocytic differentiation.
| Materials and Methods|| |
All procedures included in the study adhered to the ethical standards of the Declaration of Helsinki 1964 and its seventh revision from 2013 and obtained ethical approval from the Committee on Ethics for Scientific Research, Medical University – Varna “Prof. Dr. Paraskev Stoyanov” (protocol no. 20) on April 26, 2012.
Fourteen cases of tumors with astrocytic differentiation were included in the study and blindly evaluated in two rounds by separate pathologists for their WHO grade and tumor type. The patients provided their informed consent. Cases included were selected over a period of 6 calendar months (January–June 2015) and included eight male and seven female patients, with an age range of 16–74 years.
The presence of CD34 cells was evaluated using the automated immunohistochemistry detection algorithm of Qupath v0.2.0-m4 (University of Edinburgh, Edinburgh, UK) over an area of 76 mm with blood vessels excluded from the analysis. In superficial tumors, another 76-mm area in the subpial part was further evaluated. The data and patient survival were analyzed for statistical significance with MedCalc v19.1 (MedCalc Software bvba, Ostend, Belgium), using the Kaplan–Meier method, with differences assessed by the log-rank test. Cases corresponding 95% confidence intervals were estimated by Cox regression models, and two-tailed P< 0.05 was considered statistically significant.
| Results|| |
The 14 cases of tumors included 11 GBMs, two gliosarcomas, and one WHO Grade II astrocytoma; due to the small sample size, only the GBMs were subjected to statistical analysis.
Six of the tumors were superficial with subpial areas and were included for subpial estimation as well. Survival across all GBM samples varied from 1 to 48 months.
[Figure 1] shows the presence of cells on histology. The percentage of deep tumor CD34 cells varied from 0.7% to 21.7% and in the subpial areas from 0.87% to 12.8%.
|Figure 1: CD34-positive cells in glioblastoma multiforme. (A) CD34-positive cells (arrows) located deep into the tumor, next to the outlined blood vessels from the CD34 marked endothelial cells (original magnification, ×200). (B) CD34-positive cells (arrows) located in the subpial area (original magnification, ×100)|
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There was no statistical significance in patient survival in superficial and deep tumors (P = 0.243) [Figure 2]. Due to the small sample size, no comparison could be made for superficial tumors with a high percentage of CD34 subpial cells and those with low number of CD34 cells.
|Figure 2: Kaplan–Meier curve for patient survival in deep and superficial tumors, no statistical significance (P = 0.243)|
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The Kaplan–Meier curve for all GBMs with a cutoff of 3.6% CD34 cells revealed no statistical significance in patient survival (P = 0.076) [Figure 3].
|Figure 3: Kaplan–Meier curve for patient survival in tumors with high and low amounts of CD34-positive cells (3.6% cutoff value), no statistical significance (P = 0.076)|
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| Discussion|| |
Neural progenitor cells in GBMs are a valuable research tool as they represent a distinguished cell population, aggregated diffusely into the tumor parenchyma. These cells are important both in the development of the tumor and the migration of the tumor cells across the healthy parenchyma as the reactivation of progenitor properties allows these cells to migrate through the axon projections and blood vessels – a phenomenon widely seen in glial tumors and the embryonic development of the central nervous system.
Despite CD34-positive cells being only a fraction of the phenotypical progenitor cells in the central nervous system and glial tumors, they represent an integral part in the development and progression of glial tumors. Furthermore, their natural suppression under the pia mater may provide clues for glioma growth restriction.
Some studies have widely suggested that CD34 expression and overexpression is associated with high-grade gliomas as well as higher expression in the giant cell glioblastoma tumor type.,,
The small sample size makes it difficult to properly estimate the independent survival effect of CD34 progenitor cells in GBMs and other entries, regardless of WHO grade, on patient survival. This makes it difficult to properly evaluate the presence of any survival effect in the GBM sample; furthermore, the effect on individual WHO 2016 revision groups should also be considered.
| Conclusion|| |
Despite the specific patterns of growth and diffuse spread of CD34 progenitors in GBMs, their percentage does not correlate with the patient survival. Still, CD34 progenitor cells remain the cells of interest due to their potential role in the treatment of GBM.
Financial support and sponsorship
Institutional review board statement
The study was approved by the Committee on Ethics for Scientific Research, Medical University – Varna “Prof. Dr. Paraskev Stoyanov,” Protocol no. 20 , on April 26, 2012.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials would not be published, and due efforts would be made to conceal their identity, but anonymity cannot be guaranteed.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]