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ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 6  |  Page : 1476-1481

Yet another utility for isocitrate dehydrogenase.1: Can it serve as an immunomarker to assess tumor margins in gliomas?


1 Department of Pathology and Laboratory Medicine, All India Institute of Medical Science, Rishikesh, Uttarakhand, India
2 Department of Internal Medicine, Northeast Ohio Medical University, Canton Medical Education Foundation, Ohio, USA
3 Department of Pathology, Sri Ramachandra Medical College and Research Institute, Chennai, Tamil Nadu, India
4 Department of Pathology, Medical Trust Hospital, Kochi, Kerala, India

Date of Submission06-Jan-2017
Date of Decision15-Jun-2017
Date of Acceptance25-Feb-2018
Date of Web Publication26-Oct-2018

Correspondence Address:
Shaline Rao
Department of Pathology and Laboratory Medicine, All India Institute of Medical Science, Virbhadra Road, Rishikesh - 249 201, Uttarakhand
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_22_17

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 > Abstract 


Background: Isocitrate dehydrogenase-1 (IDH1) mutation is now an established early event in gliomagenesis. The ability to detect this mutation by several techniques including immunohistochemistry makes it a significant marker for diagnosing and prognosticating gliomas. This study was done to assess the expression of mutant IDH1 in different grades of gliomas and evaluate its utility in differentiating reactive gliosis from glioma and defining surgical margins of these tumors in the operative specimens.
Materials and Methods: A total of fifty cases including equal number of Grade I, II, III, and IV gliomas and gliosis were included in the study. Formalin-fixed, paraffin-embedded tissue sections from these lesions were immunostained with IDH1 and Ki-67 antibody, and percentage of tumor cells that stained positive with these markers was assessed.
Results: Grades II, III, and IV showed consistent immunopositivity for IDH1. No immunostaining was noted in Grade I glioma and gliosis. Mean Ki-67 labeling index correlated with grades of gliomas with low activity in Grade I and high activity in Grade IV. Individual tumor cells infiltrating into adjacent normal brain parenchyma also stained positive with IDH1 antibody.
Conclusion: Immunostaining for IDH1 mutation can be utilized as a reliable marker in the precise diagnosis of diffuse gliomas and also in objective assessment of surgical margins to differentiate gliomas from gliosis.

Keywords: Glioma, infiltration, isocitrate dehydrogenase-1, surgical margin


How to cite this article:
Rao S, Rajkumar A, Sundaram S, Joyce ME, Duvuru P. Yet another utility for isocitrate dehydrogenase.1: Can it serve as an immunomarker to assess tumor margins in gliomas?. J Can Res Ther 2020;16:1476-81

How to cite this URL:
Rao S, Rajkumar A, Sundaram S, Joyce ME, Duvuru P. Yet another utility for isocitrate dehydrogenase.1: Can it serve as an immunomarker to assess tumor margins in gliomas?. J Can Res Ther [serial online] 2020 [cited 2021 Sep 20];16:1476-81. Available from: https://www.cancerjournal.net/text.asp?2020/16/6/1476/244205




 > Introduction Top


Gliomas are the most common primary malignant tumor of the central nervous system (CNS) with highly invasive and destructive properties. Over the years, several discoveries have been instrumental in elucidating cancer biology in solid tumors, with a significant contribution toward their therapy. However, unlike other solid tumors, very little has changed with respect to treatment modalities and prognosis in malignant gliomas. The recent discovery of isocitrate dehydrogenase (IDH) enzyme mutation has widened our understanding of gliomas, especially its evolution, progression, and response to therapy. Point mutation in genes encoding IDH1 and IDH2 has been implicated in Grade II, III and secondary gliomas.[1] This mutation results in alteration in cellular metabolism and response to hypoxic and oxidative stress causing intracellular accumulation of hypoxia-inducible factor-1α (HIF-1α).[1] IDH mutations also have a definite effect on prognosis and predict tumor response to radiation and/or alkylating chemotherapy.[2] Studies have shown that IDH1 mutation can modulate the efficacy of antitumor treatment increasing its value as a novel marker having diagnostic as well as prognostic significance.

IDH1 mutation can be detected by immunohistochemistry on formalin-fixed tissues using monoclonal antibody against IDH1 R132H or by polymerase chain reaction; similarly, the increased levels of 2-hydroxyglutarate (2-HG) in IDH-mutated tumors can be detected by noninvasive magnetic resonance spectroscopy (MRS).[1],[3],[4],[5],[6]

IDH1 mutation is presently being used for classification of gliomas as per the 2016 World Health Organization (WHO) Classification of Tumors of the Central Nervous System. The WHO Grade II diffuse astrocytomas (DAs) and WHO Grade III anaplastic astrocytomas are now each categorized into IDH-mutant, IDH-wild-type, and not otherwise specified (NOS) categories. Prognosis of the IDH-mutant cases appears more favorable in both grades. Astrocytomas with more circumscribed growth pattern, showing absence of IDH gene family alterations and frequent presence of BRAF alterations (pilocytic astrocytoma and pleomorphic xanthoastrocytoma) or TSC1/TSC2 mutations (subependymal giant cell astrocytoma), are distinct from diffuse gliomas. Review of literature reveals that in most studies, IDH1 has been dealt in reference to its positivity and negativity in gliomas. Its main use as per various studies highlights its role in prognostication for gliomas. However, our study in addition emphasizes it to be a useful marker even for surgical margins.

This study was done to compare the expression of mutated IDH1 in various grades of gliomas and reactive gliosis. Another objective was also to assess the role of IDH1 as a potential marker in delineating the operative margins in neurosurgical specimens of tumor tissue.


 > Materials and Methods Top


A total of 50 cases comprising of 40 gliomas and 10 glioses were randomly selected from case files of the Pathology Department of a university teaching hospital in southern India. Gliomas selected consisted of equal number of the WHO Grade I, II, III, and IV tumors (based on the 2007 WHO classification). Immunohistochemistry was performed on tissue sections using supersensitive polymer horseradish peroxidase detection system. A 4 mm thick section was cut and taken onto a 0.1% poly-L-lysine coated. Slides were kept on slide warmer at 60° centigrade for 30 min for tissue section adherence to glass slide. Section was then deparaffinized in xylene for 10 min followed by two changes in absolute alcohol and then two changes in 70% alcohol and then rinsed gently in running water. For antigen retrieval, the slides were placed in the 0.01 M citrate buffer at a pH of 6.0 and pressure cooked at about 103 kPa/115 and at 120°C. The slides were immediately washed with distilled water followed by Tris buffer solution and then incubated in 3% hydrogen peroxide to ensure blockage of endogenous peroxidase. This was followed by rinsing in distilled water for 5 min and then in Tris buffer following which power block was added for 10 min. The slides were then incubated with primary antibody for 1 h which included IDH1 R132H (Clone H09, Isotype IgG2a, Dilution 1:20; Dianova, Hamburg, Germany) and for Ki-67 immunostaining with prediluted monoclonal mouse antihuman antibody to Ki-67 antigen (Clone: BGX-297; Isotype: IgG1 kappa, BioGenex). Secondary antibody was added and slides were incubated for 60 min. Following this, a diaminobenzidine chromogen substrate for detection of reaction was added, and finally, the slides were counterstained with hematoxylin for 3 min. Sections were then examined under microscope at ×4, ×10, ×20, and ×40 magnification to detect immunoreactivity.

Immunostain with IDH1 R132H was considered positive when tumor cells showed cytoplasmic staining. It was graded based on staining character, 0 if no staining, weak/faint stain was 1+, moderate staining was 2+, strongly positive was 3+, and intense staining was 4+ positivity. Endothelial cells, blood cells, and macrophage were not considered positive even if there was staining with IDH1. Immunoreactivity to Ki-67 was considered positive when tumor cells showed nuclear positivity. Ki-67 labeling index (Ki-67 LI) was expressed as percentage of positively stained tumor nuclei among 1,000 tumor cells. Lymphoid cells served as an intrinsic positive control for Ki-67 marker.


 > Results Top


Pilocytic astrocytoma constituted all of the Grade I tumors. Grade II tumors included 6 cases of DAs, 1 oligoastrocytoma (NOS), 1 pilomyxoid astrocytoma, and 2 oligodendrogliomas. In Grade III gliomas, there were 6 anaplastic astrocytoma, 2 Grade III oligoastrocytoma, and 2 Grade III oligodendrogliomas (NOS). The mean proliferative index of Grade I glioma and gliosis was found to be <1%, and for Grades II, III, and IV, it was 3.6%, 18.7%, and 29.2%, respectively [Table 1].
Table 1: Ki-67 labeling index in gliomas and gliosis

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Pilocytic astrocytoma did not show any expression of IDH1 immunostain. As far as Grade II, III, and Grade IV gliomas, IDH1 positivity was noted in 80% of the cases [Table 2]. Positivity was noted in DA – Grade II, oligoastrocytoma (NOS) – Grades II and III, oligodendrogliomas – Grades II and III, anaplastic astrocytoma – Grade III, and glioblastoma – Grade IV [Figure 1]. One case of pilomyxoid astrocytoma showed positive staining with IDH1. Six cases were negative for IDH1 immunostain and included one case of DA (Grade II), one case of Grade II oligodendroglioma [Figure 2], one case of Grade III oligodendroglioma, one case of anaplastic oligoastrocytoma (NOS), and two glioblastomas. In few Grade III and IV gliomas, focal positivity was noted for IDH1. Staining intensity with IDH1 ranged from weak to intense [Figure 3] in all cases of gliomas. Few cases showed heterogeneous staining pattern with respect to staining intensity in different areas of tumor tissue. Fibrillary areas showed background staining in few cases. Infiltrating individual tumor cells showed positivity with IDH1 in adjacent brain tissue [Figure 4]. The mean age of patients in the different gliomas with immunopositivity was variable [Table 3].
Figure 1: Section from glioblastoma with moderate staining in cytoplasm of tumor cells (IDH1 immunostain ×100)

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Figure 2: Section from oligodendroglioma (WHO Grade II) with moderate immunopositivity in cytoplasm (IDH1 immunostain ×100)

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Figure 3: Tissue section from glioblastoma with highly atypical cells with strong cytoplasmic positivity (IDH1 immunostain ×200)

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Figure 4: Cytoplasmic positivity in individual tumor cells of diffuse astrocytoma (WHO Grade II) highlights tumor cell infiltration in adjacent brain tissue (IDH1 immunostain ×100)

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Table 2: Isocitrate dehydrogenase-1 immunostain expression in gliomas and gliosis

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Table 3: Isocitrate dehydrogenase-1-positive gliomas and their age distribution

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 > Discussion Top


Several studies in the recent past have been directed toward genetic and epigenetic changes in an attempt to understand the pathobiology of gliomas. Quite recently, few studies have shown that gliomas harbor mutations in the genes for IDH1 and IDH2.[4] IDH functions to maintain the cellular reduction–oxidation state and is important in cellular defense against oxidative stress. IDH1 mutations have also been observed in prostatic cancer and cholangiocarcinoma as well as in hematological malignancies such as acute myelogenous leukemia, acute lymphoblastic leukemia, malignant melanoma, and primary myelofibrosis.[7],[8] Somatic mutations of IDH1 have been found in Ollier disease and Maffucci syndrome, and both these conditions have an increased propensity for malignancy.[9]

Mechanism by which IDH1 mutation results in tumorigenesis still remains unclear. Many genetic derangements have been discovered, but the most prominent one is the mutation involving CGT > CAT transitions in codon 132 that replaces the arginine residue with histidine (R132H IDH1).[9] This enzyme site is critical for isocitrate binding and mutation at R132 inactivates the enzyme's ability to bind isocitrate and thereby terminating its normal catalytic activity. The result is a reduction in the levels of α-KG and NADPH, the main cofactor needed to maintain normal levels of reduced glutathione to counteract effect of reactive oxygen species.[4],[9] Previous studies suggested that the mutant protein functions in a dominant-negative way by heterodimerizing to wild-type IDH1 and impairing its action.[10],[11] In vitro studies have revealed that the mutated IDH1 enzyme attains the ability to convert α-KG to (R)-2 HG.[12],[13],[14] An elevated level of 2-HG levels in gliomas containing an IDH1 mutation supports this theory and suggests that IDH1 is possibly an oncogene and 2-HG is an oncometabolite.[13] Studies have also highlighted that there is reduction in enzyme product α-KG in cultured tumor cells with mutant IDH1, and this, in turn, causes increase in levels of HIF-1α. hypoxia-inducible factor-1α is a transcription factor that stimulates tumor growth when oxygen is low and its stability is regulated by levels of α-KG. HIF-1α levels were consistently higher in human gliomas harboring an IDH1 mutation.[11]

It has also been found in several studies that almost all gliomas with an IDH mutation also feature either a p53 mutation or a 1p/19q co-deletion. Review of literature favors that IDH mutation possibly occurs as an early biological event during gliomagenesis and is followed by p53 or 1p19q deletion which decides progression of the disease to astrocytoma or oligodendroglioma, respectively.[1],[15],[16],[17] IDH1 mutation can also serve as a prognostic indicator. Gliomas that harbor mutation of IDH1 and IDH2 have better prognosis as compared to gliomas with wild-type IDH1. Traditionally, age of patient, grade of tumor, and MGMT methylation status are considered prognostic markers of glioma; however, with the recent advances in the molecular genetics of gliomas, IDH1 mutation status may be included as a prognostic marker to guide selection for therapy and monitor progress.[18] Another large study showed a direct correlation with IDH mutation and MGMT promoter hypermethylation and an inverse association between IDH mutations and epidermal growth factor receptor (EGFR) amplification.[19] The inverse relation with EGFR mutation can account for a low proliferative activity of the gliomas rendering it a favorable prognosis. This same study also observed co-deletion of chromosome 1p/19q in oligodendroglial tumors which is associated with a good prognosis and increased responsiveness to chemotherapy. Very recently, another mutation in the TERT (Telomerase reverse transcriptase) promoter, which results in enhanced telomerase activity and lengthened telomeres, is described in Grade IV astrocytoma as well as Grade II oligodendroglioma.[20] These new developments may pave way for reclassifying gliomas, based on tumor biomarkers which will then define pathways for developing more precise treatments.

There are several methods to identify IDH1 mutation in gliomas. While genomic polymerase chain reaction and sequencing remain the gold standard for IDH mutation testing, development of a monoclonal antibody against IDH1 R132H allows the detection of this mutation in gliomas by immunohistochemistry from paraffin-embedded sections.[1],[21],[22] The 2-HG oncometabolite has a distinctive magnetic resonance spectrum that can be detectable by in vivo MRS. This technique is noninvasive, can be performed in vivo, and repeated several times, and hence, MRS-derived information regarding the IDH status is now being frequently used for neurosurgical planning.[23]

In the current study, we evaluated occurrence of IDH1 mutations in different grades of gliomas and gliosis. Previous studies on IDH1 mutations demonstrated that it may feature in DA, oligodendroglioma, and mixed oligoastrocytoma (NOS) of WHO Grades II and III.[1],[17],[24],[25] Although approximately 70% of DA and secondary glioblastoma multiforme (GBM) harbor IDH1 mutations, this alteration is observed in fewer than 10% of primary GBM.[25],[26] Parsons et al. in their study reported that mutations of IDH1 occur more frequently among secondary GBM and young patients with GBM.[27] In our study, mutant IDH1 expression was noted in 80% of Grade II to IV gliomas, suggesting that it is a common event in gliomas. We found that grade of tumor had no relationship to percentage expression of mutant IDH1. Our study did not show 100% positivity in any grades or subtypes of tumor. A study by Thota et al. found that IDH mutation was common in DA (100%), anaplastic astrocytoma (92.8%), and secondary glioblastoma (83.3%) but infrequent in primary GBM (2.4%).[28] However, many other studies show variable positivity for IDH1 in different types of gliomas.[25],[29],[30] Our cases showed high percentage of positivity in each grade of glioma. In a similar study from North India, Jha et al. found IDH1 mutation in 46% of gliomas with 68.5% positivity in Grade II, 85.7% in Grade III, and 12.8% in secondary glioblastomas.[31] We believe that the difference in IDH1 positivity by immunohistochemistry in different studies could be related to how the tumor was sampled or could also possibly be related to ethnic variation in the population studied.

IDH1 positivity can further aid in distinguishing primary GBM from secondary. Few studies have suggested it to be a molecular marker for secondary GBM. Other studies have shown positivity in primary glioblastoma although percentage positivity was found to be less as compared to secondary glioblastoma. Hence, this mutation cannot be utilized as a marker for distinguishing primary glioblastoma from secondary glioblastoma.[25],[26],[32] Two cases of GBM in our study were found to be negative for mutant IDH1. However, p53 and EGFR were not done in our study to subclassify glioblastoma as primary or secondary. IDH1 mutation was also noted more frequently among younger patients.[30] However, our study did not reveal any association with age, a finding similar to Parsons et al.[27]

As per Louis et al. in summary of the 2016 World Health Organization Classification of Tumors of the Central Nervous System mentions glioblastoma, IDH mutant accounts to about 10% of cases, which corresponds to secondary glioblastoma with a history of preceding history of lower grade glioma.[33] Our finding showed high percentage of IDH1 positivity and may be representing secondary glioblastoma, and a finding similar to Chen et al. in their meta-analysis suggested that approximately 70%–80% of secondary glioblastomas have somatic mutation in the IDH1 gene, which are absent in primary glioblastoma.[34]

Immunomarkers such as p53 and proliferative index Ki-67 are widely accepted markers to differentiate gliosis and low-grade gliomas. Not all p53 mutations show immunoexpression in low-grade gliomas, and in these cases, IDH1 may possibly aid in diagnosis when combined along with Ki-67 LI. A study done by Horbinski et al. described no immunopositivity in nonneoplastic conditions resembling glioma.[3] A similar finding was noted by Camelo-Piragua et al. in their study on DA and astrocytosis.[35] In our study, none of the cases with reactive gliosis showed positivity with IDH1. Hence, we suggest that immunostaining for mutant IDH1 can be utilized as a reliable and accurate marker to differentiate low-grade DA from gliosis.

IDH1 mutation has been clearly shown to have a role in diagnosis and prognosis of gliomas; however, the direct therapeutic utility of this mutation is still debatable. Given that the IDH1 mutation is associated with a hypermethylated phenotype, there is a potential role for DNA methyltransferase inhibitors in treatment. These studies are still in the experimental phase in treatment of myelogenous leukemia and not yet substantiated in glial tumors.[36] Irrespective of advances in molecular genetics and targeted therapy, surgery remains the mainstay of treatment of glial tumors. Intraoperative diagnosis of CNS tumors and final grading of glioma is dependent on microscopic examination of tumor tissue. Although newer sophisticated technology such as intraoperative mass spectroscopy enables neurosurgeons to accurately define the operative field and tumor margins, the role of the pathologists cannot be underemphasized.[37] Demarcating tumor margin and clearly identifying areas of gliosis from tumor tissue remains a challenging task for the pathologist. An important feature noted in our study was tumor cells, infiltrating that the adjacent brain tissue was highlighted by IDH1 immunostain. Furthermore, none of low-grade gliomas and gliosis exhibited IDH1 positivity or Ki-67 activity. The ability of IDH1 immunostain to identify individual cells in less cellular areas and in edges of infiltrating tumor highlights its role in delineating the surgical margins. Ki67 LI when used concomitantly with IDH1 is very useful in providing a conclusive opinion on surgical margins.


 > Conclusion Top


Our study reiterates that IDH1 mutation is a common feature seen in Grade II to IV gliomas. When combined with Ki-67 LI, IDH1 immunostain can be very help in distinguishing reactive gliosis from diffuse gliomas and can serve as a reliable marker to assess tumor margins.

Acknowledgment

The authors would like to acknowledge and thank Dianova, Germany, for providing the IDH1 antibody used in the study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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