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CASE REPORT Bali Medical Journal (Bali Med J) 2019, Volume 8, Number 3: 569-572 P-ISSN.2089-1180, E-ISSN.2302-2914 Mitogen-activated protein kinase 3 (MAPK3) and Case Report human epidermal growth factor receptor 2 (HER2) on recurrent intracranial meningiomas: A case report Published by DiscoverSys CrossMark Doi: http://dx.doi.org/10.15562/bmj.v8i3.1509 Ridha Dharmajaya,* Abdurrahman Mouza

Volume No.: 8 ABSTRACT

Introduction: Meningiomas accounts for one-third of all adult Case: We report 39 years-old-female with recurrent meningioma. Issue: 3 central nervous system tumors and by far the most common primary The patient had tumor removal a year ago. After the first resection, intracranial tumor in adults. Despite their high prevalence, it the tumor demonstrated rapid growth with significant invasion to remains challenging to predict their biological and clinical behavior. neighboring dural tissue and brain parenchyma, which resulted in To date, it has been accepted that the extent of surgical resection impaired brain function and intracranial hypertension manifested as First page No.: 569 and histological grade are the most reliable factors to predict the severe headache, vomiting, and coma. Histopathological examination recurrence of meningiomas. HER2 and MAPK3 represent a well-known confirms a malignant meningioma (WHO grade I). The patient prognostic factor in various tumors, however only a few studies on had the second craniotomy for tumor removal, and we performed the relationship between meningioma recurrence, HER2, and MAPK3 immunohistochemical staining. The result was positive for HER2 and P-ISSN.2089-1180 expression. This report presents additional data that support the MAPK3 relationship between the expression HER2 and MAPK3 with recurrent Conclusion: HER2 and MAPK3 might be a reliable predictor of of meningioma. recurrent meningiomas. E-ISSN.2302-2914

Keywords: Immunohistochemical staining, HER2, MAPK3, recurrent meningioma. Cite This Article: Dharmajaya, R., Mouza, A. 2019. Mitogen-activated protein kinase 3 (MAPK3) and human epidermal growth factor receptor 2 (HER2) on recurrent intracranial meningiomas: A case report. Bali Medical Journal 8(3): 569-572. DOI:10.15562/bmj.v8i3.1509

Departement of Neurosurgery, INTRODUCTION Faculty of Medicine, Universitas Sumatera Utara, Medan, North Meningiomas are tumor originated from arachnoi- cancer, ovarian cancer, pregnancy, or obesity, are Sumatera, Indonesia dal cap cells of the leptomeninges, and it is by far linked to a higher incidence of meningiomas. the most common primary intracranial tumor in Exposure to cranial radiation was also documented adults. It accounts for 15-30% of all central nervous to increase the risk meningiomas, especially the system (CNS) tumors in adults. Despite their high more aggressive type.12 prevalence, it remains challenging to predict their According to WHO classification (2007), menin- biological and clinical behavior, especially regard- giomas are divided into three grades (I, II, and ing its recurrences.1 III).12 With this new grading system which includes Study regarding demographical data and its the brain invasion into the diagnostic criteria for association with meningioma recurrence shows aggressiveness, the percentage of atypical meningi- conflicting results. Several studies have reported omas grow to 20-35% of newly diagnosed menin- higher recurrence rates in male patients compared giomas. This classification is important because to female patients.2–6 However, other studies, have together with the extension of resection, it may found no significant difference in gender for recur- help in predicting the recurrence rate and thus the rence rates.4,5,7,8 Nakasu et al. and several other global prognosis.13 authors reported no association between tumor To date, it has been accepted that the extent of * Correspondence to: development in young patients (< 40 yrs) and a surgical resection and histological grade are the Ridha Dharmajaya, Departement of 9–11 Neurosurgery, Faculty of Medicine, high likelihood of recurrence. However, Perry most reliable factors that help predict the recur- Universitas Sumatera Utara, Medan, and associates found a strong relationship between rence of meningiomas.14–16 However, the quest North Sumatera, Indonesia. age and recurrence, while Adegbite and colleagues to search a marker to predict its clinical behavior [email protected] demonstrated that gender and age have no signifi- continued. The potential candidates were HER2 cant association with recurrence.4,9 and MAPK3. Both HER2 and MAPK3 represents Received: 2019-04-21 It has been proposed that certain medical condi- a well-known prognostic factor in various tumors Accepted: 2019-06-04 tion, including hormone replacement therapy and such as breast carcinomas.14–16 However, there are Published: 2019-12-01 hormone-related disease or state such as breast only a few studies on the relationship between

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meningioma, HER2, and MAPK3 expression, and the results are conflicting as well. This report aimed to present a case that supports the relationship between the expression HER2 and MAPK3 with recurrent of meningioma.

CASE REPORT A thirty-nine years-old female with recurrent meningioma that had craniotomy tumor removal a year ago (Figure 1 and 2). Patient came back to the hospital one-year after the surgery, with decreased Figure 3 C linical photos show bulging defect on consciousness, intracranial hypertension, and bulg- the head one-year after the first surgery ing defect on the head (Figure 3). Histopathologic examination result Meningothelial Meningioma (WHO Grade I). Head CT Scan contrast shows the isodense lobulated lesion, with homogeny enhancement. The patient had second craniotomy tumor removal, and histopathologic examination of the sample taken during surgery confirm the presence of Meningothelial Meningioma (WHO Grade I). Based on the second pathologic sample, we performed immunohistochemical staining. We used c-erbB-2 Oncoprotein (SP3) Rabbit Monoclonal Antibody with catalog number RMAB008R manufactured by Diagnostic Biosystems and Anti-ERK1 antibody [Y72] with catalog number (ab32537) manufactured by Abcam. The result from immunohistochemical staining showed positive expressions of HER2 and MAPK3 (Figure 4).

Figure 4 Photomicrograph immunohistochemical staining of HER2 (upper) and MAPK3 (lower) DISCUSSION HER2 (erbB-2) is a transmembrane glycoprotein with tyrosine kinase activity which is known as a member of the human epidermal growth factor receptor (HER/EGFR/ERBB) family. Known as an oncogene, amplification or over-expression of Figure 1 Head CT-Scan Pre-Operation shows parasagittal meningioma, this gene has been shown to play an essential role with contrast homogenous enhancement in the development of certain types of cancer.17–21 After discovering its role as an oncogene in human carcinoma and its association with the aggressive form of the cancer, researchers pay more atten- tion to HER2 in cancer research for the past two decades. Since then, a lot of studies had confirm the overexpression of HER2 in several types of cancer, including breast cancer, ovarian cancer, and gastric cancer.19,21–25 The MAPK/ERK cascade also plays a role in the initiation and regulation of meiosis, mitosis, Figure 2 H ead CT-Scan performed one-month (left) and one-year (right) and postmitotic functions in differentiated cells after surgery, show a mass on the right frontal region by phosphorylating several transcription factors.

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Activation of MAPKs is a common event in many Previous studies show over-expression of HER2 signal transduction pathways. At least six important may promote human meningioma cell proliferation pathways the has been identified to utilize different and invasion, both in vivo and in vitro. Therefore, MAPK for signal transduction. Numerous studies expression of HER2 affects meningioma develop- have shown that MAPK1/ERK2 and MAPK3/ERK1 ment and progression. These findings may explain, play an important role in the MAPK/ERK signal- in part, the association between increased HER2 in ing cascade.26 Mitogen-activated protein kinase human meningioma cells with the high recurrence (MAPK) pathway dysregulation is implicated in potential and poor prognosis. Furthermore, the >30% of all cancers, rationalizing the development present report showed support for the hypothesis of RAF, MEK and ERK inhibitors.17 that HER2 signaling and the activity of MAPK3 There were few studies that already support (ERK) involved cell proliferation and invasion of the association of HER2 and aggressive form of meningioma. These data indicated that the HER2- Meningioma. In a study conducted by Loussouran RAS-MAPK pathway to a certain extent might be a et al., HER2 immunostaining was detected in 10 potential for the development of novel therapeutic (28.5%) out of 35 meningiomas. They also reported approaches.17,28 a significantly higher rate of tumor recurrence At present, for the majority of cases, surgical in HER2-positive, compared to HER2-negative resection remains the most reliable choice in treat- meningiomas.25 Torp et al. reported a higher ratio ing meningioma. Total resection gives the best (63%) of HER2-positive meningiomas, but their result for the cure of the tumor and has the least study has some limitations: 1) they applied immu- chance of recurrence while subtotal resection may nostaining on frozen sections, 2) they investigated significantly increase the postoperative recurrence a small number of meningiomas.22 Other studies rate. Although total resection is the preferred by Andersson et al. also demonstrated a high rate choice, it may not always feasible due to some of HER2 expression in meningiomas. However, factors such as extent, location, and bony or dural there was a conflicting result from Potti et al. that infiltration.16 suggested HER2 overexpression has no role as a Possible alternative nonsurgical treatments of prognostic factor in meningiomas based on their recurrent meningiomas have been explored. The finding that HER2 was found in a very low rate.23,24 most frequently used of nonsurgical managements A study conducted by Wang, et al. in 2016 are radiotherapy and chemotherapy. At present, reported that overexpression of HER2 might there is no single consensus that states the role of promote human meningioma cell proliferation radiotherapy and chemotherapy in therapeutic and invasion in vivo and in vitro, which may affect management.15,20,27 Nevertheless, radiotherapy is the meningioma development and progression.17,19 considered important in WHO grade III meningio- Furthermore, those study recorded the correlation mas, due to its potential for recurrence and aggres- between HER2 signaling and the activity of MAPK sive characteristic. Chemotherapy has not shown (ERK) in cell proliferation and invasion. Another any convincing effect on atypical and anaplastic study demonstrated that high expression of HER2 meningiomas and should be reserved for a recur- was associated with an increase of tumor grades rent case which shows no response to all standard and recurrence rate.21 These results may explain, therapies.14,15 in part, the association between increased HER2 in human meningioma cells with the high recurrence CONCLUSION potential and poor prognosis. Determination by using MTT, colony forma- The mechanisms and factor related to recurrence tion, and Edu labeling assays found that when of meningiomas are still poorly understood. The gene expression of HER2 was downregulated, the recurrence of intracranial meningiomas might proliferative ability of the cells declined. In terms indicate unfavorable prognosis, and multiple of the cell cycle, these cells were arrested at the surgical resections are required for the treatment. G0/G1-phase, and apoptosis was increased. When The results of our case report support the role of the gene expression of HER2 was upregulated, the HER2 and MAPK3 in recurrent meningioma. A proliferation ability of the cells increased, and the better understanding of this pathway is required to invasive and migration abilities increased signifi- explain the pathology and develop a novel thera- cantly. The cell cycle was promoted at the G1/S- peutic approach. phase, and apoptosis was decreased. Therefore, those study demonstrated that HER2 promoted cell CONFLICT OF INTEREST proliferation and invasion and inhibited apoptosis in the human malignant meningioma cells.9,25–27 All authors declare no conflict of interest.

Published by DiscoverSys | Bali Med J 2019; 8(3): 569-572 | doi: 10.15562/bmj.v8i3.1509 571 CASE REPORT

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