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| CASE REPORT |
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| Year : 2022 | Volume
: 70
| Issue : 4 | Page : 1639-1642 |
Intracranial Myxoid Mesenchymal Tumour with EWSR1-ATF1 Fusion Sans Myxoid Stroma – Report of A Newer Entity with Brief Review of Literature
Salman T Shaikh, Debasish Hajra, Sashriya Singh, Santhosh Nagaraju, Hussien El-Maghraby
Department of Neurosurgery, University Hospital Coventry and Warwickshire, Clifford Bridge Road, Coventry, CV2 2DX, United Kingdom
| Date of Submission | 19-Sep-2021 |
| Date of Decision | 26-Nov-2021 |
| Date of Acceptance | 27-Nov-2021 |
| Date of Web Publication | 30-Aug-2022 |
Correspondence Address:
Salman T Shaikh
University Hospital Coventry and Warwickshire, Clifford Bridge Road, Coventry, CV2 2DX
United Kingdom
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0028-3886.355080
Intracranial myxoid mesenchymal tumors (IMMTs) are a relatively new group of tumors, first described in 2017. We report this rare variant in a 27-year-old female which was initially suspected to be a high-grade glial neoplasm. Next-generation sequencing confirmed the presence of fusion between the FET and cAMP response element-binding (CREB) family of genes. This fusion is diagnostic of IMMT, with only 19 such cases reported so far. The authors would like to highlight the need for genomic sequencing for the diagnosis of this tumor, its propensity to recur locally, and its relatively better prognosis as compared to high-grade gliomas.
Keywords: EWSR1-ATF1, FET-CREB, intracranial, myxoid mesenchymal
Key Message: Intracranial myxoid mesenchymal tumors are a recent introduction into the WHO 2021 classification of central nervous system tumors. Genomic sequencing is paramount for diagnosis, and this group shows a high tendency to recur locally.
How to cite this article:
Shaikh ST, Hajra D, Singh S, Nagaraju S, El-Maghraby H. Intracranial Myxoid Mesenchymal Tumour with EWSR1-ATF1 Fusion Sans Myxoid Stroma – Report of A Newer Entity with Brief Review of Literature. Neurol India 2022;70:1639-42 |
How to cite this URL:
Shaikh ST, Hajra D, Singh S, Nagaraju S, El-Maghraby H. Intracranial Myxoid Mesenchymal Tumour with EWSR1-ATF1 Fusion Sans Myxoid Stroma – Report of A Newer Entity with Brief Review of Literature. Neurol India [serial online] 2022 [cited 2023 Dec 7];70:1639-42. Available from: https://www.neurologyindia.com/text.asp?2022/70/4/1639/355080 |
IMMTs were first described in 2017 and subsequently added to the WHO 2021 classification of CNS tumors under “Mesenchymal non-meningothelial tumors of uncertain differentiation.”[1] The molecular characteristic that defines them consists of a genetic fusion between members of two groups of genes, that is, FET and cAMP response element-binding (CREB). The FET protein family consists of Ewing sarcoma breakpoint region 1 (EWSR1), FUS, and TAF15, whereas the CREB protein family consists of CREB1, ATF1, and CREM.[2]
| » Case Presentation | |  |
A 27-year-old patient presented with a history of left limb focal seizures and headaches for 2 weeks. Computed tomography (CT) scan revealed a right frontal lobe intra-axial lesion with hemorrhage and ring enhancement. Whole-body scan was negative, while magnetic resonance imaging (MRI) was suggestive of 2.6 cm × 3.4 cm oval irregular lesion in the right parafalcine frontal lobe with surrounding vasogenic edema and mass effect. There was peripheral irregular enhancement and patchy areas of hemorrhage. Provisional diagnosis was suspicious of a glial neoplasm [Figure 1]. She underwent gross resection of the lesion. Intraoperatively, the tumor was adherent to the dura with yellowish appearance and presence of hemorrhage within it. Histopathological examination showed a tumor that was mitotically active [Figure 2]a with large areas of necrosis [Figure 2]b. The tumor cells had prominent cytoplasmic clearing [Figure 2]c. Integrated diagnosis was compatible with glioblastoma: wild-type IDH, wild-type ATRX, unaltered p53, no mutation in BRAF-V600E, unmethylated MGMT with Ki-67 score of 20% [Figure 2]d. Correspondingly, she was given adjuvant temozolamide and 30# of 60 Gy radiation. Follow-up MRI at 1 year showed no residue or recurrence [Figure 3]. | Figure 1: (a) MRI T2 axial image showing a 2.6 cm × 3.4 cm oval irregular space-occupying lesion in the right parafalcine high frontal lobe with surrounding vasogenic edema and mass effect. (b) MRI post-contrast axial image showing peripheral irregular enhancement. (c) MRI diffusion image showing irregular diffuse restriction. (d) MRI GRE image showing patchy areas of central and peripheral hemorrhagic products
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 | Figure 2: Histopathology image (H and E stain) showing. (a) (×400 magnification) Arrows - abnormal mitoses. (b) (×200 magnification) Large areas of necrosis. (c) (×200) Cellular tumor with prominent cytoplasmic clearing. (d) Immunohistochemistry (×200) - Ki 67 proliferation index of approximately 20%. (e) Immunohistochemistry (×200) – GFAP expressed in occasional scattered tumor cells
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 | Figure 3: Interval MRI 1 year after first surgery showing no recurrence or residual tumor (T2WI and Post Contrast sequence)
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Although she remained asymptomatic for 2 years, a surveillance MRI performed 26 months after her initial diagnosis showed marked tumor recurrence [Figure 4]. A redo exploration for further safe debulking was performed. Our neurooncology MDT decided against second-line chemotherapy as the tumor was not biologically active. MRI after 6 months of second surgery showed recurrence of the high-grade neoplasm involving the motor strip with clinical left foot drop. She was then started on second-line chemotherapy with lomustine. This had to be stopped after 3 cycles as tumor showed further progression in size, edema, and perfusion at 12 months of second surgery. As her foot weakness and paresthesia were managed with steroids, she refused surgical intervention and undertook private vaccine treatment at Onkologisches Zentrum in Koln and cannabis oil treatment as alternative measures. The tumor pathology was revisited as EWSR1-ATF1 gene fusion was identified when the sample was submitted for next-generation sequencing to identify potential therapeutic targets. Further immunohistochemical analysis on broader neuroepithelial and mesenchymal markers showed expression of CD34, CD99, and focal GFAP [Figure 2]e but S100, synaptophysin, and CD56 were negative. SMA and desmin were also negative. The tumor was also submitted to a methylation-based classifier by Epic bead chip array, which did not classify it as any of the known tumor methylation class of brain tumors. The diagnosis was then revised to the emerging novel entity of IMMT. Unusual for IMMT, tumor presented as an intra-axial lesion and did not have amianthoid-like fibers or myxoid stroma. | Figure 4: MRI after 26 months of first surgery showing recurrence of the lesion
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She recently underwent a third surgery for resection of recurrence at 19 months after the second surgery and is now clinically well at 4 years follow-up since the initial diagnosis.
| » Discussion | | |
The most common fusion reported in intracranial myxoid mesenchymal tumors is between EWSR1 and CREB1. Among the 19 proven cases of intracranial myxoid mesenchymal tumors (IMMT) reported in the literature, more than 50% of cases show EWSR1–CREB1 fusion, whereas only four cases show EWSR1–ATF1 [Table 1].[3],[4],[5],[6] Interestingly, all cases apart from EWSR1-ATF1 fusion show amianthoid-like fibers. | Table 1: Intracranial myxoid mesenchymal tumor cases with EWSR1-ATF1 fusion described in the literature
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Many of the soft tissue sarcomas possess similar genetic fusions but different histological make-up. There exists some confusion with regards to similar genetic alteration seen in a different entity of tumors, namely angiomatoid fibrous histiocytoma (AFH). It has been frequently debated whether both these tumor groups should be considered as part of the same spectrum of disease. Along with AFH, these genetic fusions also occur in pulmonary myxoid sarcoma, gastrointestinal clear cell sarcoma, and salivary gland clear cell carcinoma.[7] There have been case series reported with EWSR1-CREB fusion tumors showing histological profiles both similar and dissimilar to AFH.[3],[8] AFH have not been explicitly categorized in the new WHO classification of CNS tumors and hence we have not included previous such cases in our description.
On analysis of the four similar fusion cases in the literature, it is seen that there is no specific age predilection with age ranging from 12 to 67 years. The longest follow-up is 7 years and 6 months from diagnosis. The tumor is predominantly solid, firm, and fibrous in nature and can be found adherent to the dura masquerading as a meningioma on frozen section analysis. There has been one case presenting as a cystic frontal lobe tumor with a solid nodule. Recurrence was reported in two cases, with adjuvant radiation given in both the patients. Proliferation indices have been variably reported.
Though this pathology, along with tumors of similar genetic profile, show multiple recurrences with better overall survival than high-grade glioma, the description of cases is still inadequate to make a firm conclusion on its prognosis. ESR might have a role to play in predicting its recurrence.[9],[10] Due to the relative novelty in their description, there exists no fixed regime for adjuvant treatment. There has been an isolated report mentioning the successful use of targeted immunotherapy viz. tyrosine kinase inhibitor.[2] The authors recommend surgical excision followed by adjuvant radiation therapy for optimal local control as the primary goal of treatment irrespective of the proliferation indices.
| » Conclusion | | |
Our case stands distinct in emphasizing the propensity of primary intracranial myxoid mesenchymal tumors with EWSR1-ATF1 fusion to recur locally necessitating a close and prolonged follow-up. Molecular and immunohistochemistry evaluation with gene sequencing via fluorescence in situ hybridization or polymerase chain reaction may be considered imperative for diagnosis. Retrospective re-evaluation of suspect myxoid mesenchymal tumors will help in a better understanding of the disease.
Abbreviations
CNS, Central nervous system; CT, Computed tomography; MRI, Magnetic resonance imaging.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| » References | | |
| 1. | Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, et al. The 2021 WHO classification of tumors of the central nervous system: A summary. Neuro Oncol 2021;23:1231-51.  |
| 2. | De Los Santos Y, Shin D, Malnik S, Rivera-Zengotita M, Tran D, Ghiaseddin A, et al. Intracranial myxoid mesenchymal neoplasms with EWSR1 gene rearrangement: Report of 2 midline cases with one demonstrating durable response to MET inhibitor monotherapy. Neurooncol Adv 2021;3:vdab016. |
| 3. | Kao YC, Sung YS, Zhang L, Chen CL, Vaiyapuri S, Rosenblum MK, et al. EWSR1 fusions with CREB family transcription factors define a novel myxoid mesenchymal tumor with predilection for intracranial location. Am J Surg Pathol 2017;41:482-90. |
| 4. | Sciot R, Jacobs S, Calenbergh FV, Demaerel P, Wozniak A, Debiec-Rychter M. Primary myxoid mesenchymal tumour with intracranial location: Report of a case with a EWSR1-ATF1 fusion. Histopathology 2018;72:880-3. |
| 5. | Ballester LY, Meis JM, Lazar AJ, Prabhu SS, Hoang KB, Leeds NE, et al. Intracranial myxoid mesenchymal tumor with EWSR1-ATF1 fusion. J Neuropathol Exp Neurol 2020;79:347-51. |
| 6. | Ward B, Wang CP, Macaulay RJB, Liu JKC. Adult intracranial myxoid mesenchymal tumor with EWSR1-ATF1 gene fusion. World Neurosurg 2020;143:91-6. |
| 7. | Valente Aguiar P, Pinheiro J, Lima J, Vaz R, Linhares P. Myxoid mesenchymal intraventricular brain tumour with EWSR1-CREB1 gene fusion in an adult woman. Virchows Arch 2021;478:1019-24. |
| 8. | Bale TA, Oviedo A, Kozakewich H, Giannini C, Davineni PK, Ligon K, et al. Intracranial myxoid mesenchymal tumors with EWSR1-CREB family gene fusions: Myxoid variant of angiomatoid fibrous histiocytoma or novel entity? Brain Pathol 2018;28:183-91. |
| 9. | Strojnik T, Smigoc T, Lah TT. Prognostic value of erythrocyte sedimentation rate and C-reactive protein in the blood of patients with glioma. Anticancer Res 2014;34:339-47. |
| 10. | White MD, McDowell MM, Pearce TM, Bukowinski AJ, Greene S. Intracranial myxoid mesenchymal tumor with rare EWSR1-CREM translocation. Pediatr Neurosurg 2019;54:347-53. |
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1]
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