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ORIGINAL ARTICLE Table of Contents   
Year : 2010  |  Volume : 53  |  Issue : 4  |  Page : 605-610
Determining the relationship between "microvessel density" and different grades of astrocytoma based on immunohistochemistry for "factor VIII-related antigen" (von Willebrand factor) expression in tumor microvessels


1 Department of Pathology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
2 Department of Pathology, School of Medicine, Arak University of Medical Sciences, Arak, Iran
3 Department of Pathology, School of Medicine, Gilan University of Medical Sciences, Rasht, Iran

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Date of Web Publication27-Oct-2010
 

   Abstract 

Background: Astrocytic brain tumors are the most common primary central nervous system tumors, which are classified into four grades. One of the most important pathologic criteria for the diagnosis of higher-grade astrocytomas (especially glioblastoma multiforme) is microvessel proliferation, particularly in the form of glomeruloid complex. Because tumor angiogenesis is a necessary factor for growth and invasiveness of malignancies, microvessel density (MVD) and intensity of angiogenesis may be used to determine the grade of astrocytomas and plan therapy accordingly. We have planned this study to evaluate the relationship between vwf expression in microvessels and different grades of astrocytoma. Materials and Methods: Sixty-four formalin-fixed and paraffin-embedded blocks of surgical specimens with diagnosis of astrocytoma (grades I to IV, each of them 16 blocks) were selected in a simple-nonrandom sampling. Thin sections of tissue blocks underwent immunohistochemical staining for vwf. The stained slides were examined using a light microscope at low (100) and high (400) magnifications. MVD was estimated by calculating the mean number of stained microvessels in three areas of highest vascularization in the high-power field (400). The intensity of staining was determined based on a 3 scale model, in which scores 0, 1, 2, and 3 mean no detectable stain, trace staining, moderate amount of diffuse stain, and strong diffuse staining, respectively. Results: Thirty-six (56%) patients were male and 28 (44%) were female. Scores 0 and 1 of microvessel staining intensity were not observed in any grades studied, but severe staining intensity (score 3) was observed in 18.8%, 37.5%, 56.3%, and 87.5% of grades I, II, III, and IV astrocytomas, respectively. "Vwf vessel index" (MVD staining intensity of microvessels) was 23.84, 25.62, 31.62, and 62.43 in grades I, II, III, and IV astrocytomas, respectively. Conclusion: We found a significant relationship between staining intensity of vwf in microvessels and different grades of astrocytomas. The intensity of microvessel stain increases in parallel with increasing tumor grade. Regarding "microvessel density" and "vwf vessel index," the difference is predominantly between grade IV and all other grades. However, there is no other statistically meaningful difference between grades I, II and III.

Keywords: Astrocytoma, microvessel density, von Willebrand factor

How to cite this article:
Mahzouni P, Mohammadizadeh F, Mougouei K, Moghaddam NA, Chehrei A, Mesbah A. Determining the relationship between "microvessel density" and different grades of astrocytoma based on immunohistochemistry for "factor VIII-related antigen" (von Willebrand factor) expression in tumor microvessels. Indian J Pathol Microbiol 2010;53:605-10

How to cite this URL:
Mahzouni P, Mohammadizadeh F, Mougouei K, Moghaddam NA, Chehrei A, Mesbah A. Determining the relationship between "microvessel density" and different grades of astrocytoma based on immunohistochemistry for "factor VIII-related antigen" (von Willebrand factor) expression in tumor microvessels. Indian J Pathol Microbiol [serial online] 2010 [cited 2019 Dec 11];53:605-10. Available from: http://www.ijpmonline.org/text.asp?2010/53/4/605/71996



   Introduction Top


Astrocytomas are the most common primary central nervous system (CNS) tumors, classified into four histologic types: pilocytic astrocytoma (grade I), diffuse fibrillary astrocytoma (grade II), anaplastic astrocytoma (grade III), and glioblastoma multiforme (grade IV). [1],[2],[3]

Pilocytic astrocytoma (WHO grade I) generally presents in childhood and adolescence. [4] It has the best prognosis among astrocytomas, but it rarely shows atypical behavior such as local recurrence or malignant transformation. [5] The contrast enhancement of pilocytic astrocytoma in a computed tomography (CT) scan or magnetic resonance imaging (MRI) is characteristic. [6] Mitosis is nil or difficult to see and the MIB-l labeling index is not generally >1-3%. [7] The 10-year survival of patients with supratentorial pilocytic astrocytomas is 100% after total resection. [8]

Diffusely infiltrating astrocytomas (WHO grade II) are the largest group of astrocytic tumors. [9] One of the major problems of diffuse astrocytomas is the high incidence of anaplastic transformation, with more than 50% risk of progression. [10]

Anaplastic astrocytomas (WHO grade III) are composed of cells with small, dark, and pleomorphic nuclei as well as abnormal tumor vessels. [11] The lack of coagulation necrosis and/or microvascular (endothelial) proliferation distinguishes anaplastic astrocytomas from glioblastomas. [12] The average survival of patients with anaplastic astrocytoma is 2 years. [13]

Glioblastoma multiforme (WHO grade IV) is a very aggressive tumor. [14] There are primary and secondary variants, the latter resulting from expansion of particularly aggressive clones generated within pre-existent, differentiated astrocytic neoplasms. [15] Glioblastoma multiforme is highly cellular, with nuclear pleomorphism and mitotic activity. Complex microvascular hyperplasia is common in many glioblastomas due to tumor-derived mitogens such as vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF), in which proliferating blood vessels are transformed into glomeruloid or solid tufts. This phenomenon involves some vessel-associated cell types, such as pericytic/myoid cells. [16],[17]

One of the most important pathologic criteria for the diagnosis of higher grades of astrocytomas (especially glioblastoma multiforme) is microvessel proliferation (particularly in the form of glomeruloid complex). [1],[18] Some authors believe that neoplastic cells in higher grades of astrocytomas have the potential to transform into microvessels, but this is a controversial issue. [17],[19],[20] Factor VIII-related antigen (von Willebrand factor; vwf), an important factor in hemostasis, is one of the endothelial-related markers that can be studied by immunohistochemistry. [21] It has been said that microvessel density (MVD) is a prognostic indicator of astrocytomas, and expression of endothelial-related markers (such as vwf) by neoplastic cells has a direct relationship with the grade of astrocytomas. [22],[23] Because tumor angiogenesis is a necessary factor for growth, invasiveness, and recurrence of malignancies, determination of MVD will be helpful in the grading of astrocytomas. Moreover, it can be used to plan therapy by prescribing anti-angiogenesis drugs to achieve better prognosis and survival.

The present study has been designed to determine the relationship between astrocytoma grade and microvessel status of the tumor based on immunohistochemical evaluation of vwf in tumor microvessels.


   Materials and Methods Top


In this descriptive-analytical study, 64 formalin-fixed and paraffin-embedded surgical specimens with unequivocal diagnosis of astrocytoma (grades I-IV, each of them 16 blocks) were selected in a simple-nonrandom sampling. Histological classification and grading were assessed based on the World Health Organization system. [4],[9] Three-micron sections were prepared and stained by the immunohistochemistry technique using anti-vwf antibody (DAKO, Denmark) based on the standard protocol recommended by the manufacturer.

After staining with vwf antibody, slides of tumors as well as positive and negative controls were examined. The slides were first observed at low power (100 objective) to detect areas with maximal staining quality and then at high power (400 objective) to estimate MVD. We estimated, subjectively, the following two parameters: (1) MVD, by calculating the mean number of stained vessels in three areas of highest vascularization (400 magnification) and (2) intensity of staining for microvessels on a scale of 0-3, in which 0 means no detec table stain, 1 means trace staining, 2 means a moderate amount of diffuse stain, and 3 means strong diffuse staining. [9]

By multiplying MVD by staining intensity of endothelial and/or pericytic cells of microvessels, we defined a parameter named "vwf vessel index."

Unfortunately, we did not have access to information regarding the patients' follow-up and survival to determine the relationship between tumor microvessel status and survival.

All the data were analyzed using SPSS software and statistical indices (mean, standard deviation, and standard error). Relationship between qualitative variables was determined by the chi-square test. Based on the Leven and Kolmogronove-Smirnov tests, we used the Scheffe statistical test to compare the grades two-by-two for the microvessel-related parameters.


   Results Top


Thirty-six (56%) patients were male and 28 (44%) were female (Chart 1).[Additional file 1]

68.75% of grade I, 62.5% of grade II, 56.25% of grade III, and 37.5% of grade IV astrocytomas were found in females. The difference between frequencies of various grades of astrocytoma among females was not statistically significant (P = 0.3) (Chart 2).[Additional file 2]

Mean age of the patients was 33 (x 4) years. Mean age of the patients with grades I, II, III, and IV astrocytoma was 10, 36, 38, and 46 years, respectively. A statistically significant difference was observed between mean age of various grades of astrocytoma (P = 0.001). Analysis by the Scheffe test for two-by-two comparison of groups showed that this statistically significant difference is predominantly due to difference between grade I and other grades (P = 0.001) (Chart 3).[Additional file 3]

The MVD was 10.87 (8.69-13.05), 10.62 (8.07-13.17), 12.31 (9.97-14.64), and 21.25 (14.95-27.54) in grades I, II, III, and IV astrocytomas, respectively. Statistically, the MVD is different in various grades (P = 0.001) [Figure 1], [Figure 2], [Figure 3], [Figure 4]. This is predominantly due to the difference between grade IV and the other grades (P < 0.01) [Table 1].
Figure 1 :Microvessel density (determined by vwf staining) in grade 1 astrocytoma (pilocytic astrocytoma) (IHC, ×100)

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Figure 2 :Microvessel density (determined by vwf staining) in grade 2 astrocytoma (diffuse fibrillary astrocytoma) (IHC, ×100)

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Figure 3 :Microvessel density (determined by vwf staining) in grade 3 astrocytoma (anaplastic astrocytoma) (IHC, ×100)

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Figure 4 :Microvessel density (determined by vwf staining) in grade 4 astrocytoma (glioblastoma multiforme) (IHC, ×200)

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Table 1 :Microvessel density (MVD) in different grades of astrocytoma


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Regarding staining intensity of the microvessels, scores 0 and 1 were not observed in any grades studied, but severe intensity (score 3) was seen in 18.8%, 37.5%, 56.3%, and 87.5% of grades I, II, III, and IV astrocytomas, respectively. Statistically, these rates are different among various grades (P = 0.001). The intensity of microvessel stain increases in parallel with increasing tumor grade [Table 2].
Table 2 :Staining intensity of microvessels for vwf in different grades of astrocytoma


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The mean values of "vwf vessel index" were 23.84 (18.64-29.1), 25.62 (18-33.24), 31.62 (24.54-38.70), and 62.43 (42.84-82.03) in grades I, II, III, and IV astrocytomas, respectively. These mean values are statistically different among various grades (P = 0.001). The Scheffe test for two-by-two comparison of the grades showed that this finding is only due to the difference between grade IV and the other grades (P < 0.002) [Table 3].
Table 3 :"vwf vessel index" (MVD staining intensity of microvessels) in different grades of astrocytoma


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   Discussion Top


Generally, the relationship between MVD and different grades of astrocytoma has not been studied yet in a comprehensive and broad-based manner. There are only a few studies about MVD in some but not all grades of astrocytoma. Most of these studies have shown that MVD increases in higher grades of astrocytoma and that it is a prognostic indicator of astrocytoma. [24],[25],[26]

Abdulrauf et al. [24] used the immunohistochemistry method to evaluate microvessel status in low-grade astrocytomas by factor VIII and VEGF. They observed that patients with more than seven microvessels in tumor tissue had a significantly shorter survival time compared with those with seven or fewer microvessels. Tumors having a larger number of microvessels also had a greater risk of undergoing malignant transformation. They introduced MVD as an independent prognostic indicator of survival in fibrillary low-grade astrocytoma. [24]

Yue and Chen [25] examined vasculogenic mimicry by CD34 endothelial marker periodic acid-Schiff (PAS) dual staining in grades II, III, and IV astrocytomas and reported the existence of vasculogenic mimicry phenomenon in some malignant astrocytomas.

Rojiani and Dorovini-Zis [26] studied factor VIII-related antigen expression in glioblastoma multiforme and indicated that glomeruloid vascular channels in glioblastoma multiforme are complex structures devoid of astrocytic end-feet, which are lined with hyperplastic endothelial cells showing an altered morphological phenotype and supported by the basal lamina and pericytes.

Some other studies have revealed positive vwf reaction in neoplastic cells of astrocytomas. Nowacki and Tabaka [27] studied factor VIII-related antigen expression in grades II and IV of astrocytomas and concluded that at least some of the neoplastic glial cells within the glioblastoma multiforme may express factor VIII-related antigen, and that their location near the glomeruloid vascular proliferations might suggest their potential functional relationship with endothelial cells.

It is supposed that tumor angiogenesis and vascular density can be used as determinants of radiosensitization and response to anti-angiogenesis drugs, and also as prognostic markers. [24]

Birlik et al. [28] studied the prognostic significance of tumor vascularity in pediatric and adult astrocytomas. In contrast to pediatric astrocytomas, vascularity in adult astrocytomas correlated significantly with postoperative survival by univariate analysis. MVD was shown to be an independent prognostic factor by multivariate analysis.

In the present investigation, we have conducted a study in which all grades of astrocytomas have been included with equal sample volume. We estimated not only "microvessel density" but also the staining intensity of vwf (factor VIII-related antigen) in the endothelial and/or pericytic cells of microvessels by immunohistochemistry. In addition, we defined an index named "vwf vessel index," which is very useful in predicting the grade of astrocytomas.

Our results show significantly higher MVD and "vwf vessel index" in glioblastoma multiforme (grade IV) in comparison with all other grades of astrocytomas. However, there is no statistically meaningful difference between grades I, II, and III.

Regarding the staining intensity of microvessels, we found that the intensity of microvessel stain increases in parallel with increasing tumor grade

According to the results obtained, we suggest the evaluation of vwf expression in astrocytomas, especially when grade determination is problematic. Moreover, the data concerning microvessel status in astrocytomas can be used by clinicians in planning therapy, using anti-angiogenic drugs in tumors with higher MVD. This study shows the usefulness of "vwf vessel index" determined by immunohistochemistry in the evaluation of various grades of astrocytic brain neoplasms. However, further studies with larger sample volumes and using more endothelial cell markers (such as CD31, CD34 or VEGF) are needed to validate the sensitivity and specificity of vessel-related markers in grading astrocytomas. Efforts must be taken to develop more sensitive methods such as computerized and morphometric image analysis for precise evaluation of endothelial cell markers expression. Further studies may also more accurately reveal the relationship between angiogenesis and prognosis of astrocytomas. It is of importance to determine whether in the same grade, tumors with higher real or potential angiogenesis have a worse prognosis. The benefit of anti-angiogenic drugs in astrocytic tumors with considerable MVD may be also the subject of future studies.

As mentioned above and as a conclusion, we found a significant relationship between intensity staining of vwf in microvessels and different grades of astrocytomas. The higher the grade, the greater the intensity of staining for vwf (factor VIII-related antigen). About MVD and "vwf vessel index," the difference is predominantly between grade IV and all other grades, but there is no statistically meaningful difference between grades I, II, and III.

 
   References Top

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Correspondence Address:
Kourosh Mougouei
Department of Pathology, School of Medicine, Isfahan University of Medical Sciences, Isfahan
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.71996

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    Figures

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    Tables

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