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  Table of Contents    
ORIGINAL ARTICLE  
Year : 2011  |  Volume : 54  |  Issue : 4  |  Page : 683-687
The prognostic impact of O 6- methylguanine DNA methyltransferase and epidermal growth factor receptor expressions on primary gliosarcoma: A clinicopathologic and immunohistochemical study of seven cases at a single institution


1 Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
2 Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine; E-Da Hospital, I-Shou University, Kaohsiung, Taiwan

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Date of Web Publication6-Jan-2012
 

   Abstract 

Context: Gliosarcoma is an uncommon variant of glioblastoma characterized by a biphasic tissue pattern of glial and mesenchymal differentiation. O 6- methylguanine DNA methyltransferase (MGMT) is a DNA repair protein that removes mutagenic and cytotoxic adducts from O 6 -guanine in DNA. Lack of MGMT protein expression immunohistochemically is related to drug responses in patients of malignant glioma treated with alkylating agents. Epidermal growth factor receptor (EGFR) is the most frequently amplified gene in glioblastoma and associated with tumor invasiveness, angiogenesis, poor survival, and resistance to radiation therapy. Aims: To elucidate the relationship between the statuses of the MGMT as well as EGFR proteins and the prognosis. The study was undertaken on samples received at the Department of Pathology from 2003 to 2009. Materials and Methods: Clinicopathologic and immunohistochemical study of seven cases was performed. Results: This series included three men and four women with a mean age of 49.3 years at first surgery. The median progression-free survival (PFS) was 22.2 months and 8.6 months for primary tumors with 0 to 1+ and 2+ to 3+ MGMT staining, respectively; the median overall survival (OS) was 27.5 months and 14.2 months for primary tumors with 0 to 1+ and 2+ to 3+ MGMT staining, respectively. The median PFS was 17.2 months and 11.2 months for primary tumors with 0 to 1+ and 2+ to 3+ EGFR staining, respectively; the median OS was 20.4 months and 17.7 months for primary tumors with 0 to 1+ and 2+ to 3+ EGFR staining, respectively. Conclusions: The series showed that MGMT and EGFR protein expressions were both unfavorable prognostic factors for patients with gliosarcoma.

Keywords: Epidermal growth factor receptor, gliosarcoma, O 6 -methylguanine DNA methyltransferase

How to cite this article:
Lin JW, Wu YT, Chang IW. The prognostic impact of O 6- methylguanine DNA methyltransferase and epidermal growth factor receptor expressions on primary gliosarcoma: A clinicopathologic and immunohistochemical study of seven cases at a single institution. Indian J Pathol Microbiol 2011;54:683-7

How to cite this URL:
Lin JW, Wu YT, Chang IW. The prognostic impact of O 6- methylguanine DNA methyltransferase and epidermal growth factor receptor expressions on primary gliosarcoma: A clinicopathologic and immunohistochemical study of seven cases at a single institution. Indian J Pathol Microbiol [serial online] 2011 [cited 2019 Oct 14];54:683-7. Available from: http://www.ijpmonline.org/text.asp?2011/54/4/683/91491



   Introduction Top


Gioblastoma is the commonest malignant primary brain tumor with predominant astrocytic differentiation. While most of the variants are merely descriptive, some, however, have unique clinical presentations or prognostic implications and gliosarcoma is among the latter. Histopathologically, gliosarcoma is made up of both malignant glial and mesenchymal components in a biphasic pattern.

Alkylating agents are the most effective cytotoxic regimens in treating malignant gliomas'. However, only half of the patients respond to alkylating drugs. [1],[2] The DNA-repair enzyme O 6 -methylguanine-DNA methyltransferase (MGMT) is a key factor in resistance to alkylating agents. [3] Silencing of the gene encoding MGMT by promoter methylation has been investigated as an independent favorable prognostic factor for patients of glioblastoma receiving alkylating agents such as temozolomide. [4],[5],[6] Researches on target therapies with epithelial growth factor receptor (EGFR) kinase inhibitors for glioblastoma have also been done. [7],[8]

To investigate the prognostic value of the expression status of MGMT and EGFR and the possible role of certain chemotherapeutic agents and target therapies for gliosarcoma, we conducted the current study.


   Materials and Methods Top


Between 2003 and 2009, there were nine cases of gliosarcoma diagnosed at Department of Pathology. Two were excluded; one with inadequate tissue from stereotactic biopsy, the other with postirradiation secondary gliosarcoma developed from glioblastoma. As a result, seven cases of gliosarcoma were enrolled in the present study. Clinical data, which included age, sex, location of involvement, treatment, and clinical follow-up, were obtained from the medical records. Routine hematoxylin-eosin-stained sections were generated from formalin-fixed, paraffin-embedded tissue which was cut to three μm thick.

Immunohistochemical stains were performed using standard reagents and techniques on an i6000 Automated Staining System (BioGenex, San Ramon, CA, USA). The following antibodies were used for immunohistochemistry: Glial fibrillary acidic protein (GFAP) (clone ZCG29, Carlsbad, Invitrogen, CA, USA; steam in citrate buffer, 1:150), S-100 (polyclonal, Dako, Carpinteria, CA, USA; 1:1000), vimentin (clone V9, Neomarkers, Fremont, CA, USA; steam in citrate buffer, 1:400), desmin (clone DE-R-11, Novocastra, Newcastle upon Tyne, UK; steam in citrate buffer, 1:100), cytokeratin high molecular weight (HMW) (clone 34βE12, Neomarkers; steam in citrate buffer, 1:100), cytokeratin low molecular weight (LMW) (clone AE1, Neomarkers; steam in citrate buffer, 1:100), epithelial membrane antigen (EMA) (clone GP1.4, Novocastra; steam in citrate buffer, 1:400), CD34 (clone QBEnd/10, NeoMarkers; steam in citrate buffer, 1:400), MIB-1 antigen (clone MIB-1, Dako, steam in citrate buffer, 1:100), O 6 -methylguanine-DNA methyltransferase (MGMT) (clone MT 3.1, NeoMarkers; steam in citrate buffer, 1:40), and epithelial growth factor receptor (EGFR) (clone EGFR.25, Novocastra; steam in citrate buffer, 1:50). Inactivation of endogenous peroxidase activity was obtained by incubating sections in 3% H 2 O 2 for 15 min. Localization of bound antibodies was performed with a non-biotin polymeric technology (Super Sensitive TM Polymer-HRP Detection System; BioGenex). Immunoreactions were visualized using 3, 30-diaminobenzidine tetrahydrochloride (ZYMED® ; Invitrogen, Carlsbad, CA, USA). Appropriate positive controls for each antibody were run in parallel. For evaluation of MGMT and EGFR, the immunostained slides were assessed for both extent and intensity of staining. The percentage of tumor with positive staining was estimated first. Next, the intensity of staining was semiquantitatively scored from 0 to 3+. The rough percentage of tumor with positive staining and the semiquantitative measure of staining intensity were then tabulated for each specimen [Table 1].
Table 1: Clinical data and MGMT and EGFR statuses

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Progression-free survival (PFS) interval was defined as the period from first diagnosis to first local recurrence or metastasis. Overall survival (OS) interval was calculated from date of surgery to date of death.


   Results Top


Clinical Course

The essential clinical information of all seven cases is summarized in [Table 1]. This series included three men and four women with a mean age of 49.3 years at first surgery. These tumors were distributed in sites where gliosarcomas' normally occur, including temporal (71%) and parieto-occipital (19%). The tumors ranged from 2.1 to 5.4 cm in diameter and the mean diameter was 4.2 cm. The common initial symptoms included headache, dysarthria, seizure attack, and hemiparesis.

Clinical follow-up after diagnosis was available for all patients. All patients had gross total resection at the first surgery and underwent radiotherapy postoperatively with median dose of 6,069 cGy (5,580-6,660 cGy). Six patients (86%) received concomitant-adjuvant temozolomide chemotherapy. All patients died eventually. The median overall survival (OS) was 16.6 months. One patient (case no. 6) died of infection without evident tumor progression. Six patients (86%) had tumor progression. The median progression-free survival (PFS) was 13.1 months. No metastasis was found. For the six patients who suffered tumor progression, three patients (cases no. 2, 4, 5) underwent reoperation followed by additional chemotherapy, and the other three (cases no. 1, 3, 7) were treated with additional chemotherapy alone.

Light Microscopy and Immunohistochemistry

There were ten primary and recurrent gliosarcoma specimens totally. The pathologic features and histochemical and immunohistochemical characteristics are illustrated in [Figure 1] and [Figure 2]. All tumors showed a biphasic pattern with distinct gliomatous and sarcomatous components. Gliomatous differentiation was evidenced by presence of anaplastic astrocytic cells along with necrosis and microvascular proliferation, thus fulfilling the criteria for glioblastoma. The tumor cells of gliomatous element were positive for GFAP and S100 immunohistochemically. The sarcomatous morphology was characterized by densely packed long bundles of spindle cells, typical of fibrosarcoma. No heterologous mesenchymal differentiation of bony, chondroid, muscular or lipomatous lineage was found. The tumor cells of sarcomatous element were positive for reticulin stain.
Figure 1: Photomicrographs of resected tissue from first surgery (case 2). (a) Showing features of glioblastoma with necrosis (HandE, ×200), (b) Showing features of fibrosarcoma (H and E, ×200), (c) Demonstrating a biphasic pattern with distinct gliomatous and sarcomatous components (H and E, ×100), (d) The sarcomatous component is positive for reticulin (reticulin, ×100), (e) The gliomatous component is immunoreactive with GFAP (IHC, ×200), (f) The gliomatous component is immunoreactive with S100 (IHC, ×200), (g) Showing nuclear staining of MGMT in the gliomatous component overshadowed by that of sarcomatous component (IHC, ×200), (h) Showing stronger membranous and cytoplasmic staining of EGFR in the sarcomatous component than that of gliomatous component (IHC, ×200)


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Figure 2: Photomicrographs of resected tissue (case 1). (a) Showing features of glioblastoma with necrosis (H and E, ×100), (b) Showing features of fibrosarcoma (H and E, ×100), (c) Showing nuclear staining of MGMT in the gliomatous component (IHC, ×200), (d) Showing nuclear staining of MGMT in the sarcomatous component (IHC, ×200), (e) Showing stronger membranous staining of EGFR in the gliomatous component (IHC, ×200), (f) Showing weaker membranous staining of EGFR in the sarcomatous component (IHC, ×200)

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Immunohistochemically, regarding gliomatous component, one tumor (10%) exhibited 3+ nuclear staining for MGMT protein, six (60%) exhibited 2+ staining, one (10%) exhibited 1+ staining, and two (20%) exhibited 0 staining. If based solely on sarcomatous component, two tumors (20%) exhibited 3+ nuclear staining for MGMT protein, five (50%) exhibited 2+ staining, one (10%) exhibited 1+ staining, and two (20%) exhibited 0 staining. Excluding case no. 6 who died of infection, the median progression-free survival (PFS) was 22.2 months and 8.6 months for primary tumors with 0 to 1+ and 2+ to 3+ MGMT staining, respectively; the median overall survival was 27.5 months and 14.2 months for primary tumors with 0 to 1+ and 2+ to 3+ MGMT staining, respectively. The MGMT immunostains tended to be stronger following tumor recurrence.

On the part of EGFR immunostains, regarding gliomatous component, two tumors (20%) exhibited 3+ membranous staining for EGFR protein, four (40%) exhibited 2+ staining, three (30%) exhibited 1+ staining, and one (10%) exhibited 0 staining. If based solely on sarcomatous component, three tumors (30%) exhibited 3+ membranous staining for EGFR protein, three (30%) exhibited 2+ staining, two (20%) exhibited 1+ staining, and two (20%) exhibited 0 staining. Excluding case no. 6 who died of infection, the median progression-free survival (PFS) was 17.2 months and 11.2 months for primary tumors with 0 to 1+ and 2+ to 3+ EGFR staining, respectively; the median overall survival was 20.4 months and 17.7 months for primary tumors with 0 to 1+ and 2+ to 3+ EGFR staining, respectively. The intensities of EGFR immunostains were similar between primary and recurrent tumors.


   Discussion Top


O 6 -methylguanine DNA methyltransferase (MGMT) is a DNA repair protein that removes mutagenic and cytotoxic adducts from O 6 -guanine in DNA. Methylation of discrete regions of the CpG island of MGMT gene is associated with the silencing of the gene. [9],[10] Inactivation of MGMT gene by promoter hypermethylation was detected in 40% of gliomas' and colorectal carcinomas and in 25% of non-small cell lung carcinomas, lymphomas, and head and neck carcinomas. [11] It was suggested that epigenetic inactivation of MGMT plays an important role in primary human neoplasia. [11] DNA-repair enzyme MGMT is also a key factor in resistance to alkylating agents, because the transfer of alkyl groups to MGMT prevents the formation of lethal cross-links in DNA. [3],[12] Therefore, the MGMT protein is also known as O 6 -alkylguanine-DNA alkyltransferase. The deficiency of the enzyme may increase the sensitivity of brain tumors to alkylating agents. [13],[14] In the study of Esteller et al.,[15] MGMT promoter methylation in glioma was associated with regression of the tumor and prolonged overall and disease-free survival. It was an independent prognostic factor for the patient with carmustine treatment in this study. In another study by Hegi et al.,[6] not only a survival benefit was observed in patients treated with temozolomide and radiotherapy among patients whose tumor contained a methylated MGMT promoter, but also MGMT promoter methylation was an independent favorable prognostic factor irrespective of treatment. In a study on glioblastoma, Parkinson et al.[16] also found a good correlation between the increasing MGMT promoter methylation and decreased MGMT protein expression.

There have been few studies on the relationship between MGMT promoter methylation or protein expression and survival of patients with gliosarcoma. [17],[18] According to Kang et al.,[18] there was no statistical significance between MGMT protein expression and OS although patients with methylated MGMT promoter had better prognosis than patients with unmethylated MGMT promoter with respect to OS and PFS. In our study, the median progression-free survival (PFS) was 22.2 months and 8.6 months for primary tumors with 0 to 1+ and 2+ to 3+ MGMT staining, respectively; the median overall survival (OS) was 27.5 months and 14.2 months for primary tumors with 0 to 1+ and 2+ to 3+ MGMT staining, respectively. The results showed that decreased MGMT protein expression was a favorable prognostic factor, similar to the finding of Parkinson et al.[16] in their research on glioblastoma.

The intracellular tyrosine kinase of the epidermal growth factor receptor (EGFR) activates signaling cascades leading to cell proliferation, angiogenesis, and inhibition of apoptosis. [19] EGFR is the most frequently amplified gene in glioblastoma, [20] occuring in approximately 40% of cases. Amplification of the EGFR gene is associated with several variants of structural alterations, in which, the most common being variant III (EGFRvIII). [21] EGFR amplification in glioma has been associated with tumor invasiveness, angiogenesis, poor survival, and resistance to radiation therapy. [22],[23] Target therapies with EGFR kinase inhibitors for glioblastoma have been investigated in phase II clinical trials. [7],[8] In early clinical trials, 10% to 20% of malignant glioma patients seemed to derive benefit from the EGFR inhibitor gefitinib. [24] Evaluations of the relationship of EGFR protein expression immunohistochemically to EGFR gene amplification have been done on glioblastoma and rendered a good correlation between the presence of EGFR amplification and immunostaining intensity of EGFR expression. [25],[26],[27],[28]

While EGFR amplification is common in glioblastoma, the rate of EGFR amplification is much lower in gliosarcoma, barely accounting for 0% to 8% of cases. [17],[28],[29],[30] As a result, it is very difficult to find any article addressing the relationship of EGFR protein expression immunohistochemically to EGFR gene amplification or their prognostic implications in gliosarcoma. [17] In our study, the median progression-free survival (PFS) was 17.2 months and 11.2 months for primary tumors with 0 to 1+ and 2+ to 3+ EGFR staining, respectively; the median overall survival (OS) was 20.4 months and 17.7 months for primary tumors with 0 to 1+ and 2+ to 3+ EGFR staining, respectively. The results showed that EGFR protein expression was an unfavorable prognostic factor.

Gliosarcoma, a morphologically defined glioblastoma variant, was original described in 1895 by Stroebe et al.[31] The tumor comprises approximately 2% of all glioblastomas and presents a biphasic pattern of glial and mesenchymal differentiation. [32],[33] Similar genetic alterations, including p53 mutations, p16 deletions, and PTEN mutations, have been found in the gliomatous and sarcomatous components indicating a monoclonal origin. [29],[34],[35] Our study demonstrated, in addition to the association between MGMT as well as EGFR protein expressions and prognosis, largely similar staining results between gliomatous element and sarcomatous one. The results might provide further evidences in proving that the two components are of the same origin.

In summary, the series showed that MGMT and EGFR protein expressions were both unfavorable prognostic factors for patients with gliosarcoma. Due to the relatively small number of our cases, the value of this work is limited. We sincerely hope that there will be more comprehensive and detailed studies concerning the impact of MGMT and EGFR protein expressions on gliosarcoma.

 
   References Top

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Correspondence Address:
I-Wei Chang
Department of Pathology, E-Da Hospital, No.1, Yida Road, Yanchao District, Kaohsiung
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.91491

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