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Year : 2021  |  Volume : 64  |  Issue : 4  |  Page : 638-643
Adjunctive role of immunohistochemical expression of Nucleostemin in differentiation of grade II and III diffuse astrocytomas

1 Department of Pathology, Eskişehir Osmangazi University School of Medicine, Eskişehir, Turkey
2 Department of Radiation Oncology, Eskişehir Osmangazi University School of Medicine, Eskişehir, Turkey
3 Department of Neurosurgery, Eskişehir Osmangazi University School of Medicine, Eskişehir, Turkey

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Date of Submission17-Feb-2021
Date of Decision04-Apr-2021
Date of Acceptance21-Apr-2021
Date of Web Publication20-Oct-2021


Aims: Astrocytomas are common tumors and grade is an important parameter in determining the treatment modalities. Tumor proliferation activity should be determined for the differentiation of grades II and III tumors. In difficult cases, an auxiliary parameter is required. Nucleostemin (NS) is nucleolar Guanosine triphosphate (GTP)-binding protein 3. It has important roles in cell proliferation, cell cycle regulation, self-renewal, and apoptosis. In this study, we investigated whether the level of NS expression is different in grades II and III astrocytomas. Settings and Design: Adults diagnosed with grades II and III astrocytomas were included in the study. Material and Methods: Paraffin blocks that best reflected tumor morphology were studied via immunohistochemical staining for NS. Only nuclear staining was evaluated; cytoplasmic staining was not considered. Statistical Analysis Used: Fisher's exact test, continuity corrections, and Pearson's Chi-square tests were used in the crosstabs. The survival analysis was based on the Kaplan-Meier method. Results: Only 20% (6/30) of grade II tumors had high intensity staining, while 54,2% (13/24) of grade III tumors had high staining intensity. NS was significantly more intense in grade III tumors than grade II tumors. In cases with high NS expression, survival was significantly shorter than the cases with low expression. Conclusion: NS is significantly higher expressed in grade III tumors than grade II tumors. In difficult cases, it can be used as a useful proliferation marker in the differentiation of grades II and III astrocytomas.

Keywords: Astrocytoma, grading, nucleostemin

How to cite this article:
Arik D, Özen A, Özkara E, Yılmaz E, Canaz F, Yıldırım GD. Adjunctive role of immunohistochemical expression of Nucleostemin in differentiation of grade II and III diffuse astrocytomas. Indian J Pathol Microbiol 2021;64:638-43

How to cite this URL:
Arik D, Özen A, Özkara E, Yılmaz E, Canaz F, Yıldırım GD. Adjunctive role of immunohistochemical expression of Nucleostemin in differentiation of grade II and III diffuse astrocytomas. Indian J Pathol Microbiol [serial online] 2021 [cited 2021 Nov 27];64:638-43. Available from: https://www.ijpmonline.org/text.asp?2021/64/4/638/328547

   Introduction Top

Diffuse astrocytic gliomas are the most common brain tumors in adults. Grade is of great importance in determining the treatment of patients. Malignant diffuse gliomas are graded as II, III, and IV by WHO according to their malignancy potential. Diffuse glioma with microvascular proliferation and/or necrosis is glioblastoma (WHO grade IV). In the current grading system, distinguishing grades II and III diffuse gliomas depends on the presence of a significant number of mitoses and anaplasia. WHO did not set a definite cut-off value in determining the mitotic number due to the differences between the observers, the difficulty of differentiating mitoses from apoptosis, the variability of the specimen quantity, and the different visual fields of different microscopes. In small specimens, it is stated that single mitosis is sufficient for the diagnosis of anaplastic astrocytoma.[1] There are also studies suggesting >2/10 high power field (HPF ) mitosis and >4/1,000 tumor cells as the cut-off value of the mitotic index.[2],[3] Additionally, in studies about proliferative index (e.g., proliferation index determined by Ki-67), a clear cut-off value has not been revealed to be used in grading. This is because even if they are of the same grade, these tumors are heterogeneous in themselves due to the different mutations they contain. Also, different laboratory dynamics and different clones used may result in no standard outcomes. Molecular classification of glial tumors has emerged recently. Rapid progress has been made in the classification of tumors, thanks to numerous studies. However, improvements could not be achieved at this rate in grading these tumors. In the 2016 WHO classification, the same grading criteria are still applied for isocitrate dehydrogenase (IDH )-mutant and IDH-wild-type astrocytic gliomas.[4],[5] While the risk of classification based on these criteria may still accurately reflect the biological behavior of the disease in IDH-wild-type tumors, it is suggested that these criteria cannot classify the risk in IDH-mutant astrocytomas.[5] IDH-mutant and IDH-wild-type tumors are different tumors and the risk classification should be updated for these two different groups. Many studies are underway to improve the risk classification. Potential morphological, proliferative, or molecular markers that may be associated with aggressive clinical behavior and provide a more clinically accurate grading have been investigated.[1],[6],[7],[8],[9],[10],[11],[12]

Molecular changes have been published, such as epidermal growth factor receptor (EGFR ) amplification, telomerase reverse transcriptase (TERT) promoter mutation, loss of cyclin-dependent kinase inhibitor 2A (CDKN2A) homozygous, which have been found to have an effect on patient survival.[11],[13],[14] Developments in molecular classification will continue to progress, and classifications will be found that can better predict the biological behavior of the tumors. However, it is still the microscopic features of the tumor that will form the basis for molecular classification and determine the risk of malignant behavior with it. In this situation, the nuclear atypia and proliferative activity of the tumor will remain important and will continue to be the features that should be specified in the pathology reports. Especially in the separation of grades II and III tumors, in cases where it is difficult to determine clearly the mitotic activity and nuclear atypia, immunohistochemical markers may be helpful.

Nucleostemin (NS) is a nucleolus-located GTPase. Its main task is related to pre-RNA regulation in ribosomal protein synthesis.[15],[16] High NS expression is associated with increased cellular proliferation potential and tumor malignancy during cancer development.[15],[17],[18] Despite the relationship between NS levels and cellular proliferation potential, the impact of NS expression and activity on tumor development is poorly understood and controversial. NS is expressed in embryonic stem cells, central nervous system stem cells, bone marrow stem cells, and testicles. It has been shown to be a necessary protein for the proliferation of stem cells and some cancer cells.[19] It is thought that NS plays an important role in cellular self-renewal, cell cycle regulation, apoptosis, and cell proliferation through the interaction with p53 and many other proteins.[17],[18] High NS expression has been found to be associated with prognosis in cervical squamous cell carcinoma, renal cell carcinoma, prostatic carcinoma, esophageal carcinoma, gastric adenocarcinoma, and breast carcinoma.[20],[21],[22],[23],[24],[25] Although there are a few studies in glial tumors, NS high expression has been reported to be associated with poor prognosis.[26] NS has also been identified as a marker of cell proliferation.[16],[23],[24]

The study aims to investigate the expression of NS, which has recently become a proliferation marker in glial tumors and to determine whether it can be used in grading. We aimed to determine whether there is an expression difference in grades II and III tumors.

   Materials and Methods Top

Patients and clinical parameters

Adult patients diagnosed with grades II and III astrocytomas, between 2012 and 2018, at our Pathology Department, were included in the study. All patients had undergone total or subtotal surgical resection. A histopathological review of the slides was performed. Grading was based on the WHO classification. Mitotic index and anaplasia were taken into account. There is no cut-off value determined by WHO for the mitotic index. While some authors consider single mitosis sufficient, some accept 2 or 4 mitotic figures as a cut-off value.[1],[27],[28] In our study, we evaluated the occurrence of single mitosis as sufficient for the diagnosis of grade III tumor. Also, 10 glioblastomas (grade IV) were included in the study. The demographic features and survival times of the cases were provided from the Neurosurgery and Radiation Oncology Departments. Our study was approved by the Non-Drug Clinical Research Ethics Board of our University.


Paraffin blocks that best reflected tumor morphology were studied via immunohistochemical staining for NS (ab70346 – Abcam, Eugene, OR, USA). Sections with a thickness of 4 μm were obtained from these paraffin blocks, and slides were deparaffinized. Immunoperoxidase staining was then completed using an automatic staining machine (the Dako Omnis Automated IHC/ISH staining system) in accordance with the manufacturer's instructions. Chromogenic diaminobenzidine (DAB) was used for signal detection, and cells were counterstained with Harris hematoxylin. Negative controls were incubated with the same concentration of immunoglobulin (IgG1; Dako, Ely, UK) instead of the primary antibody. The positive controls were testicular seminoma specimens. Only nuclear staining was evaluated; cytoplasmic staining was not considered. The level of expression was assessed by the percentage and the intensity of the immunohistochemical staining. Pannuclear strong staining was classified as severe positive, while spot or mild nuclear staining was regarded as weak positive. The expression of NS compared with the Ki-67 proliferation index (routinely determined in cases by immunohistochemical method), tumor grade, and clinicopathological features.

Statistical analysis

Fisher's exact test, continuity corrections, and Pearson's Chi-square tests were used in the 2 × 2 crosstabs. In other crosstabs, Pearson's Chi-square test was employed to evaluate the statistical association between the clinicopathologic variables and NS expression. The survival analysis was based on the Kaplan-Meier method, and statistical significance was assessed via the log-rank test. A P value of less than 0.05 was considered significant.

   Results Top

Thirty cases were grade II and 24 were grade III astrocytomas. The mean age of the patients was 41 and 43.7 in grades II and III tumors, respectively. The male to female ratio was 1.7/1. Forty-six tumors were in the hemispheres. Four of the tumors were in the thalamus, two were in the cerebellum, and two were in the spinal cord. All the patients had undergone total or subtotal surgical resection. Adjuvant therapy data were available in 48 cases. About 29 patients were given both chemotherapy and radiotherapy. Six patients had chemotherapy or radiotherapy alone. Thirteen patients did not receive any adjuvant therapy. Follow-up data were available in 48 of 54 patients. The follow-up period of the cases was 38.5 months (4–115) on average. The mean overall survival for grades II and III was 54.6 and 37.3 months, respectively.

According to the results of the immunohistochemical study, in all the cases, NS was stained in more than 10% of the tumor cells. When the staining intensity was evaluated, only 20% (6/30) of grade II tumors had high intensity, while 54.2% (13/24) of grade III tumors had high staining intensity [Figure 1] and [Figure 2]. NS was significantly more severely expressed in grade III tumors than grade II tumors (P = 0.012) [Table 1]. In grade IV tumors, NS tended to be severe staining too (9/10). Grade IV tumors are significantly higher in NS expression than grades II and III tumors (P < 0.001).
Figure 1: High expression of NS in grade III astrocytoma (X 200)

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Figure 2: Low expression of NS in grade II tumor (X 200)

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Table 1: Nucleostemin expression and tumor grade

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When the microscopic features were evaluated, no significant difference was observed in the tumors with the same nuclear grade in those with low and high NS expression. The presence of macronucleoli was relatively more common in tumors with high NS expression, but the difference was not statistically significant (P = 0.789).

The Ki-67 proliferation index was 3.3% (1–10%) in grade II tumors and 13.3% (5–25%) in grade III tumors. There was a positive correlation between Ki-67 proliferation index and NS staining intensity (P = 0.017). The mean Ki-67 proliferation index was not statistically different in the groups with high and low NS expression of grade 2 tumors (P = 0.084). In grade III cases, Ki-67 proliferation index was not different in tumors with high and low NS expression (P = 0.435). Gender, patients' age, tumor localization, the extent of resection, or adjuvant therapy status were not associated with NS expression level.

In the survival analysis, overall survival was significantly lower in patients with high NS staining intensity compared to patients with low staining intensity (P = 0.007) [Figure 3]. Disease-free survival was lower in these cases (P = 0.01). No statistical relationship was found between NS staining intensity and age of patients, tumor localization, surgical resection, and adjuvant therapy.
Figure 3: Kaplan–Meier analysis of overall survival for tumors showing low versus high NS expression

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In Univariate Cox proportional analyses, NS expression, histological grade, and Ki-67 proliferation index were associated with overall and disease-free survival. A multivariate analysis (Cox regression test) showed that NS expression levels were an independent prognostic factor [Table 2].
Table 2: Univariate and multivariate analyses results for overall and disease-free survival

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   Discussion Top

The grading of astrocytomas is practically not objective. Different systems have been proposed for the grading of these tumors over the years. WHO classification has been used recently.[29] Diffuse astrocytomas are between grades II and IV. Grade II tumors contain cellular atypia. It is diagnosed as grade III in the presence of cellular anaplasia and increased mitotic activity, and grade IV in the presence of microvascular proliferation or palisading necrosis. The fact that the grading criteria are not clear or objective increase the difficulty. It is not uncommon to have difficulty in distinguishing grades II and III tumors. The distinction between grades II and III tumors is based on the proliferative activity (such as the mitotic index), with increased cellularity and nuclear atypia. However, in this distinction, exact cut-off values for the number of mitotic figures have not been determined. This increases interobserver variability in grading and affects the clinical approach and treatment protocols.[30]

Today, a marker alone cannot perform the risk grading of diffuse gliomas alone in adult patients. In astrocytomas, mutations such as TERT, TP53, ATRX (ATP-dependent helicase), CIC (homolog of the Drosophila gene capicua), far upstream element-binding protein 1 (FUBP1) affect prognosis and can be used to determine treatment.[28],[31] Homozygous loss of CDKN2A/B has also been proposed for use in the risk classification of IDH-mutant astrocytomas.[14] Homozygous deletion significantly increases proliferative activity. Thanks to this molecular study, it is possible to avoid technical problems such as tissue artifact, fixation, and staining problems and to eliminate interobserver differences in IDH-mutant tumors.[14] CDK4 amplification and 14th chromosome loss are associated with poor prognosis.[32],[33] Phosphatidylinositol 3 kinase regulatory subunit alpha (PIK3R1) mutation,[34] platelet-derived growth factor receptor A (PDGFRA) amplification,[35] N-myc amplification,[14] high levels of copy number variations (CNV), and somatic mutations[6] have been associated with short survival. It may also be thought that some of these markers may be useful in distinguishing grades II and III tumors. However, their use in practice is quite difficult and expensive. Despite these developments and recommendations, the existing grading system remains valid. According to the molecular characteristics of the tumors, before the risk classification of the disease is made, it must be graded again according to the previous system. Tumor proliferation activity should be determined for the separation of grades II and III tumors, whether the tumor is IDH-mutant or IDH-wild-type. In difficult cases, an auxiliary parameter is required in addition to mitotic activity.

In 2016, WHO included the IDH mutation status in the classification of diffuse gliomas. IDH mutation in grades II and III tumors was detected in 85.12% of the cases. There is no mutation in 14.87% of the cases. Life expectancy in IDH-wild-type tumors is shorter compared to IDH-mutant tumors.[28] The lifespan of grades II and III tumors in the IDH-mutant tumor group was not statistically different. In these cases, the mitotic index is not different. In IDH-wild-type tumors, survival in grade II tumors is significantly higher than grade III tumors (1.97 vs 4.82 years). In these cases, the mitotic index is statistically different.[28] It is understood that IDH-mutant and IDH-wild-type tumors are different tumors. While conventional grading systems seem sufficient for wild-type tumors, this system does not reflect the clinical course in IDH-mutant tumors. Additional molecular and immunohistochemical parameters are required to be used to determine the clinical course in these tumors.

Mitotic figures are tried to be seen in the Hematoxylin&Eosin preparations in routine examination while determining the mitotic activity. In difficult cases, phospho-histone H3 (pHH3) can be used immunohistochemically to distinguish mitosis from imitative images. This marker is very useful for the detection of mitosis, but it may give a false-positive result when working in automated immunostaining systems.[1] We do not use this antibody in our clinic because of false-positive results. Even if the Ki-67 proliferation index is recommended for grading, it does not provide an exact separation of grades II and III tumors. Grade III tumors with low Ki-67 index can be found and also grade II tumors with high Ki-67 index. In addition, technical problems may be encountered in Ki-67 immunohistochemical study. For example, in old tissues stored for a long time at high temperatures, false-negativity occurs.[36] Standardization and optimization of the antigen retrieval protocols for Ki-67 are more difficult than standardizing the mitotic figure counting approach. In this case, it seems that additional adjunct markers are needed.

NS has been found upregulated in various proliferating cell types, including cancer cells and stem cells. It was thus designated as a cell proliferation marker as well as a marker for poor prognosis in cancer patients.[5],[24] Asadi et al.[37] identified high NS levels in high-grade carcinomas by Reverse transcription polymerase chain reaction (RT-PCR). They proposed that high NS levels may have a causative role in the tumorigenesis and/or progression of stomach carcinoma. However, its expression and potential functions in gliomas are still uncertain. Upregulation of NS might accelerate human glioma proliferation via the Wnt/β-catenin pathway, and related to poor 5-year-survival ratios.[26]

Although it is stated that NS can function as a proliferation marker, there is no study on the use of grading. Our work is unique in this aspect. We have demonstrated that it may be beneficial especially for brain tumors having problems in grading. Grade III tumors were expressing significantly higher NS than grade II tumors and immunohistochemical evaluation was very easy. In tumors with high NS expression, Ki-67 proliferation index was also significantly higher and the patients' survival times were shorter.

It can be considered that the weak point of the study is that the IDH mutations cannot be evaluated. Recently, other molecular and immunohistochemical markers that may affect prognosis have been published. However, our aim was to find a marker that helps grading. Cellular atypia and mitotic activity (proliferation index) are used for grading glial tumors, regardless of the tumor's IDH mutation status or molecular properties. In tumors where mitosis cannot be seen, NS can be used as an immunohistochemical auxiliary marker.

In our study, we investigated whether NS would be beneficial when determining proliferation activity. According to our results, NS is significantly higher in grade III tumors. In cases with difficulty in grading, NS may be useful in the differentiation of grades II and III and can be used as a proliferation marker.

Ethical Approval

Our study was approved by the Non-Drug Clinical Research Ethics Board of Medicine Faculty of Eskişehir Osmangazi University (16 October 2018, Order No: 19).

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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Correspondence Address:
Deniz Arik
Department of Pathology, Eskisehir Osmangazi University, Faculty of Medicine, Meselik Kampusu - 26480, Eskisehir
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpm.ijpm_183_21

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