FET-CREB fusion–positive extra-axial myxoid mesenchymal tumor in the cerebellum: illustrative case

Abstract

BACKGROUND

Myxoid mesenchymal tumor (MMT) is an exceptionally rare central nervous system (CNS) tumor, with even fewer reported cases in the cerebellum. Its complex histopathological features and nonspecific clinical presentation pose considerable challenges in diagnosis. The rarity of the tumor, coupled with its poorly characterized clinical and radiological features, complicates early detection and effective treatment.

OBSERVATIONS

xsThe authors present the case of an 18-year-old female who presented with persistent headaches and intermittent diplopia. MRI revealed a hypervascular mass in the right cerebellum, showing marked contrast enhancement. The patient underwent total tumor resection, and histopathological examination revealed lobulated tumor cells that were positive for the FET-CREB fusion gene. Immunohistochemical staining was positive for epithelial membrane antigen, vimentin, and H3K27me3, with a Ki-67 proliferation index of 8%, confirming the diagnosis of MMT. The patient had an uneventful recovery and remained recurrence free during a 6-month follow-up.

LESSONS

This case highlights the critical role of the FET-CREB fusion gene in diagnosing cerebellar MMT. It emphasizes the importance of early recognition, comprehensive pathological evaluation, and genetic analysis in managing this rare tumor. A thorough, multidisciplinary diagnostic approach is essential for determining the optimal treatment and improving patient outcomes.

https://thejns.org/doi/10.3171/CASE24872

Cerebellar myxoid mesenchymal tumor (MMT) is an extraordinarily rare and highly heterogeneous tumor of the CNS. Its nonspecific clinical presentations and imaging characteristics often complicate its differentiation from other cerebellar lesions, increasing the risk of misdiagnosis.¹ Recent advances in molecular pathology, particularly the identification of the FET-CREB fusion gene, have provided new insights into the diagnosis of MMT, playing a pivotal role in its differential diagnosis.² Studies have suggested that the presence of the FET-CREB fusion gene not only enhances diagnostic accuracy but also influences the tumor’s biological behavior and pathogenesis.³

The 2016 update to the WHO classification of CNS tumors marked a shift from relying solely on histopathological features to integrating molecular markers into the diagnostic framework.⁴ This shift highlights the growing significance of molecular alterations, such as the FET-CREB fusion, in diagnosing rare CNS tumors. The 2021 WHO revision further emphasized the importance of molecular diagnostics, improving the ability to accurately identify and classify rare tumors like MMT.⁵

This report aims to highlight the critical role of molecular markers, particularly the FET-CREB fusion gene, in the diagnosis of cerebellar MMT. Through the presentation of a rare case of an 18-year-old female with cerebellar MMT and confirmed FET-CREB fusion gene positivity, we emphasize the importance of molecular pathology in the accurate and timely diagnosis of this rare tumor. Given its complex clinical and radiological features, our case underscores the value of molecular diagnostics in distinguishing MMT from other similar cerebellar lesions. Furthermore, we explore how molecular markers can shed light on the tumor’s pathogenesis and inform clinical management strategies.

Illustrative Case

Presentation

An 18-year-old female presented to our Department of Neurosurgery with a 2-week history of dizziness, headache, and 4 days of diplopia. One month earlier, she had experienced intermittent dizziness, headache, and projectile vomiting. MRI performed at a local hospital revealed a right cerebellar lesion, suspected to be a meningioma. The patient had no prior history of similar symptoms or any family history of tumors.

On admission, the patient’s vital signs were stable, and physical examination revealed no abnormalities, with normal pupillary reflexes and limb strength. Head CT revealed an isodense mass in the right posterior fossa beneath the skull base, causing mild compression of the brainstem (Fig. 1A). Subsequent T1- and T2-weighted MRI demonstrated an isointense lesion with surrounding edema (Fig. 1B and C). Diffusion-weighted imaging (DWI) showed no evidence of restricted diffusion (Fig. 1D). Axial T1-weighted contrast-enhanced MRI revealed homogeneous enhancement of the mass, which appeared as small patchy high signals on both T1- and T2-weighted images, surrounded by edema and compressing the adjacent brainstem. Coronal T1-weighted enhanced MRI clearly showed a well-defined, lobulated mass closely related to the tentorium cerebelli, with no significant infiltrative enhancement. Sagittal T1-weighted enhanced MRI showed no thickening or enhancement of the adjacent meninges (Fig. 1E–G).

FIG. 1.

Preoperative imaging. A: Axial CT scan revealing a homogeneous density mass in the right posterior fossa, accompanied by adjacent cerebellar edema and mild brainstem compression. B and C: Axial T1-weighted (B) and T2-weighted (C) MR images showing an abnormal signal intensity lesion beneath the right occipital bone. D: Diffusion-weighted image showing no restricted diffusion. E–G: Postcontrast T1-weighted MR images demonstrating a homogeneously enhancing lesion in the right posterior fossa beneath the tentorium, with surrounding brain edema and brainstem compression. The mass is close to the tentorial structures, with well-defined margins and a lobulated shape, without significant meningeal invasion or enhancement.

The patient underwent preoperative evaluation and relevant diagnostic tests, with no surgical contraindications identified. A craniotomy was performed via a suboccipital retrosigmoid approach. Intraoperatively, a pale-red tumor with a firm texture and rich vascularity was observed. The tumor was adherent to the tentorium cerebelli, and its boundary with the adjacent cerebellar cortex was unclear, with areas of adhesion. After meticulous dissection of the tumor-brain interface, the tumor was completely excised. The resected tumor measured approximately 4 × 3 × 2 cm.

Postoperative head CT and contrast-enhanced MRI showed no significant abnormal enhancement at the surgical site, indicating a successful resection of the right posterior fossa mass (Fig. 2).

FIG. 2.

Postoperative axial images. A:Head CT scan showing successful resection of the posterior fossa mass. B:T1-weighted MR image revealing mild hyperintensity in the operative area. C:T2-weighted MR image showing no residual tumor. D:Postcontrast MR image demonstrating no significant enhancement at the surgical site.

Histopathological examination revealed that the tumor cells were arranged in lobulated clusters, exhibiting prominent cellular atypia and low mitotic activity. The tumor demonstrated myxoid degeneration and was characterized by a rich capillary network. Immunohistochemical staining was positive for epithelial membrane antigen (EMA), vimentin (VIM), and H3K27me3, further supporting its mesenchymal origin. Ki-67 staining revealed a low proliferation index, approximately 7%–8% (Fig. 3A–E). Although imaging studies such as head CT and MRI provide an initial assessment of the tumor, the imaging features of MMTs lack specificity and cannot establish a definitive diagnosis, offering only supportive evidence. Radiologically, MMT typically appears as a mass with well-defined borders, often accompanied by edema; however, these features do not significantly differ from those of other mesenchymal tumors; thus, they cannot be used as diagnostic criteria.⁶ Therefore, the role of imaging in our case was primarily as a tool for preliminary evaluation.

FIG. 3.

Histopathology images. A: High magnification showing a mitotic figure (arrow) in a tumor cell, indicating marked cellular atypia. B: Low magnification showing lobulated architecture with variable cellular density and fibrous stroma. C: Medium magnification showing focal myxoid degeneration in the tumor stroma (arrows). D: Immunohistochemistry (IHC) showing positive staining for desmin in tumor cells. (E) Ki-67 IHC indicating a low proliferation index of 7%–8%. H&E (A–C), original magnification ×400 (A), ×100 (B), ×200 (C–E).

The final diagnosis relies heavily on molecular pathological analysis, particularly gene fusion analysis and immunohistochemical marker testing, which can clarify the tumor type and its origin. Genetic testing revealed an EWSR1-ATF1 fusion gene mutation, suggesting that this alteration can play a crucial role in the tumorigenesis of MMTs. Furthermore, the tumor mutation burden was 0.55 mutations/megabase, and microsatellite instability testing showed a stable status, indicating a limited potential response to immunotherapy.⁷ The presence of the FET-CREB gene fusion represents a significant molecular feature in our case, not only providing strong support for the final diagnosis but also potentially influencing both prognosis and therapeutic decisions. Given these pathological and molecular data, Onametostat (II-D) (Johnson & Johnson) is considered a promising therapeutic option for further treatment planning.

Postoperatively, the multidisciplinary treatment team concluded that the patient had undergone complete resection of the tumor, with no indication for further targeted treatment. The medical team recommended regular follow-up examinations. Six months postsurgery, an MRI follow-up confirmed that the tumor, located in the right posterior cranial fossa beneath the tentorium, had been completely excised. No significant contrast enhancement was observed, and there were no signs of recurrence. Postoperative effects, such as mass effect and brain parenchymal edema, were effectively relieved. Additionally, the patient underwent structured rehabilitation therapy, including physical therapy, outside the hospital, resulting in significant improvement in both clinical status and symptoms compared to preoperative conditions (Fig. 4).

FIG. 4.

Six-month postoperative imaging. A–C: Axial (A), coronal (B), and sagittal (C) T1-weighted postcontrast MR images showing complete resection of the tumor in the right posterior fossa, below the cerebellar tentorium, with no enhancement and no evidence of recurrence or residual tumor. D–F: Panels E–G in Fig. 1. The white arrows indicate the tumor.

Informed Consent

The necessary informed consent was obtained in this study.

Discussion

Observations

FET-CREB fusion–positive MMT is an exceptionally rare CNS neoplasm, with only a few cases documented in the literature to date.²,⁶ First described in 2017, this tumor has drawn significant attention due to its distinct molecular and histopathological characteristics. It was officially incorporated into the 2021 WHO classification of CNS tumors. The hallmark molecular feature of MMT is the fusion of FET family genes (e.g., EWSR1 and FUS) with CREB family genes (e.g., CREB1 and ATF1), which serves as a key diagnostic marker.⁸ Among these, the EWSR1-CREB1 fusion is the most common, accounting for approximately 70% of cases, while the EWSR1-ATF1 fusion is relatively rare, with only a handful of cases reported⁹ (Table 1).

TABLE 1.

Published causes of intracranial MMT with FET-CREB fusion

Authors & Year	Age (yrs)/Sex	Location	MRI	Resection	Pathology	Recurrence	Adjuvant Tx	FU
Ward et al., 202011	48/F	Lt lat ventricle	Mixed	STR	MMT w/ EWSR1-ATF1 gene fusion	Recurrence at 4 mos; repeat op; recurrence at 1 mo	FSRT; bevacizumab for radiation necrosis	1-yr FU, no recurrence after FSRT
Kim et al., 202212	79/F	Lt temporal lobe	Mixed	PR	Brain parenchymal AFH w/ EWSR1-CREM fusion	None	None	15 mos, no recurrence
Sasaki et al., 202213	7/F	Lt parietal lobe	Mixed	GTR	MMT w/ EWSR1-CREM gene fusion	None	None	9 mos, no recurrence
Levy et al., 202214	19/F	Rt lat ventricle	Mixed	GTR	MMT w/ EWSR1-CREB gene fusion	None	None	9 mos, no recurrence
Kao et al., 201715	15/F	Meninges	Mixed	GTR	MMT w/ EWSR1-CREM fusion	None	None	17 mos, no recurrence
Kao et al., 201715	23/F	Occipital lobe	Mixed	STR	MMT w/ EWSR1-CREB1 fusion	None	RT	5 mos, no recurrence
Kao et al., 201715	20/M	Frontal lobe	Mixed	GTR	MMT w/ EWSR1-CREB1 fusion	None	None	5 mos, no recurrence
Kao et al., 201715	12/M	Frontal lobe	Solid	GTR	MMT w/ EWSR1-ATF1 fusion	None	None	12 mos, no recurrence
Vizcaino et al., 202116	50/F	Bifrontal falcine	Mixed	GTR	Angiomatoid fibrous histiocytoma w/ EWSR1-ATF1 fusion	None	None	5 mos, no recurrence
Sloan et al., 20219	15/F	Cerebral convexity (occipital lobe)	Mixed	GTR	MMT w/ EWSR1-CREB1 fusion	Local recurrence at 9 & 13 mos	None	Disease free at 36 mos post-Tx
Ballester et al., 202017	67/M	Lt temporal lobe	Mixed	GTR	MMT w/ EWSR1-ATF1 fusion	Recurrence at 4 mos	FSRT; management of radiation necrosis	1-yr FU after 2nd resection, no recurrence
Libbrecht et al., 202018	14/F	High pst frontal region, near superior sagittal sinus	Mixed	GTR	MMT w/ EWSR1-CREB1 fusion	None	None	12-mo FU, no recurrence
Komatsu et al., 202019	53/F	3rd ventricle	Mixed	STR	MMT w/ EWSR1-CREB1 fusion	Small residual tumor postop, treated w/ GKRS	GKRS (38.4 Gy)	3 mos postop, alive w/ residual tumor
Bale et al., 201820	12/M	Lt cerebellar hemisphere	Solid	GTR	MMT w/ EWSR1-CREB1 fusion	None	None	1-yr FU, no recurrence
Bale et al., 201820	14/F	Lt lat ventricle	Mixed	GTR	MMT w/ EWSR1-CREB1 fusion	None	None	1-yr FU, no recurrence
Bale et al., 201820	18/M	Rt frontal lobe	Solid	GTR	MMT w/ EWSR1-CREM fusion	None	None	1-yr FU, no recurrence
Sciot et al., 201821	17/F	Frontal lobe	Cystic	GTR	MMT w/ EWSR1-ATF1 fusion	Recurrence at 20 mos, 7 yrs	RT after 1st recurrence 59.4 Gy	7.5 yrs since Dx
Shaikh et al., 202222	27/F	Frontal lobe	Solid	GTR	MMT w/ EWSR1-ATF1 fusion	Recurrence at 26 & 32 mos	TMZ plus 59.4 Gy RT in 30 Fx after 1st op	4 yrs since Dx
Present case	18/F	Rt cerebellum	Cystic	GTR	MMT w/ EWSR1-ATF1 fusion	None	None	6 mos since Dx

AFH = angiomatoid fibrous histiocytoma; Dx = diagnosis; FSRT = fractionated stereotactic radiation therapy; FU = follow-up; Fx = fractions; GKRS = Gamma Knife radiosurgery; PR = partial resection; pst = posterior; STR = subtotal resection; Tx = treatment.

The anatomical distribution of MMT exhibits certain distinct patterns. The current literature indicates that these tumors are most frequently located in the frontal lobe, temporal lobe, or ventricular regions. In contrast, cases arising in the cerebellum are exceedingly rare, with few pathological reports available.¹⁰ This study presents a unique case of cerebellar MMT, offering a detailed description of its clinical presentation, imaging features, and molecular pathology, highlighting the rarity and unique characteristics of such tumors in this anatomical location. The diagnostic and therapeutic process in our case underscores the critical role of FET-CREB gene fusion in confirming the diagnosis of MMT and emphasizes the necessity of early identification and comprehensive pathological evaluation in managing these rare tumors. This report provides valuable insights into the diagnosis and treatment of cerebellar MMTs and contributes to the growing understanding of their molecular subtypes, offering a foundation for more precise management of these exceptionally rare neoplasms.

Histologically, intracranial MMT (IMMT) demonstrates significant heterogeneity influenced by the fusion type. Tumors with EWSR1-CREB1 fusions typically display a uniform myxoid stroma, while EWSR1-ATF1 fusions often exhibit irregular cellular arrangements and focal fibrosis, suggesting possible subclassifications within IMMT.¹⁰ This tumor can occur across a wide age range (7–79 years), with a slight predilection for younger adults (20–30 years) and females. Common anatomical locations include the frontal lobe, temporal lobe, and ventricular regions. Imaging often reveals cystic and solid components, and intraoperative findings of dural adhesion frequently lead to misdiagnosis as meningioma.

Gross-total resection (GTR) remains the primary treatment for IMMT, although recurrence rates vary by fusion type. EWSR1-ATF1 fusions are associated with a higher risk of recurrence, as highlighted by a reported case of recurrence within 4 months postsurgery that required reoperation and adjuvant radiotherapy.¹⁷ In contrast, EWSR1-CREB1 fusions are generally linked to lower recurrence rates and favorable long-term outcomes, with most patients remaining disease free for 1–2 years following complete resection.

Molecular profiling plays a pivotal role in diagnosing IMMT and tailoring treatment strategies. It not only aids in identifying specific fusion subtypes but also provides valuable prognostic insights. Studies have suggested that IMMT might involve complex signaling pathways, such as interleukin-6/STAT3, which influence tumor behavior and, in some cases, drive systemic inflammatory responses.¹,²³ These mechanisms can underpin the variable biological behavior of IMMT. For example, CREM-associated fusions are linked to aggressive phenotypes, frequently accompanied by myelin-like structural changes on imaging.⁵ In our case, immunohistochemical findings (EMA, VIM, and H3K27me3 positivity) aligned with reported features, confirming the diagnosis.²⁴

Techniques such as next-generation sequencing and genomic lineage analysis have significantly advanced diagnostic capabilities, particularly for cases with subtle or nonspecific clinical presentations. Our case of an 18-year-old female presenting with persistent headaches and diplopia highlights the diagnostic complexities associated with IMMTs.¹ FET-CREB fusion–positive IMMTs, especially those harboring EWSR1-CREB1 fusions, are typically associated with more favorable outcomes. However, when the FET and CREB genes fuse, they form fusion proteins that act as aberrant transcription factors, thereby dysregulating critical cellular pathways involved in tumorigenesis. These fusion proteins alter the expression of downstream genes, thereby contributing to the initiation and progression of mesenchymal tumors. In contrast, CREM-associated fusions tend to exhibit more aggressive clinical behavior and poorer prognosis, underscoring the distinct biological characteristics of these tumors. This distinction highlights the importance of genetic subtyping for risk stratification and personalized treatment planning.²⁴,²⁵

In light of these molecular insights, Onametostat (JNJ-64619178) emerges as a promising therapeutic agent for FET-CREB fusion–positive tumors, including our case of an IMMT. Onametostat is a selective inhibitor of protein arginine methyltransferase 5 (PRMT5), an enzyme crucial for regulating gene expression and cellular processes such as proliferation, survival, and differentiation. PRMT5 is overexpressed in various malignancies, including sarcomas, and its inhibition has demonstrated significant antiproliferative effects. In the context of FET-CREB fusion–positive tumors, the fusion proteins act as abnormal transcription factors that drive tumorigenesis and tumor progression. By targeting PRMT5, Onametostat has the potential to disrupt these aberrant transcriptional processes, offering a targeted therapeutic approach for these malignancies.

Although Onametostat has primarily been evaluated in sarcoma models and other solid tumors, its mechanism of action—modulating key cellular pathways involved in gene expression—suggests that it could also be effective in treating FET-CREB fusion–positive tumors. While clinical data specific to these tumors remain limited, preclinical studies have shown that Onametostat can effectively suppress tumor growth in cancers driven by PRMT5 overexpression. These findings provide a promising basis for further clinical investigation of Onametostat in the treatment of FET-CREB fusion–positive IMMTs.²⁶

Moreover, combining Onametostat with other therapeutic modalities, such as immune checkpoint inhibitors, can enhance its therapeutic efficacy, particularly in tumors with elevated PD-1 or PD-L1 expression. These tumors can respond to immune checkpoint blockade, and synergistic effects between Onametostat and immune therapy could not only suppress tumor growth but also promote a more robust immune response. As the molecular landscape of mesenchymal tumors becomes increasingly well understood, Onametostat’s targeted mechanism offers the potential for precision medicine, particularly in cases of residual or recurrent disease where conventional therapies might be less effective.

Given the promising mechanism of action of Onametostat, future clinical trials are essential to establish its efficacy in treating FET-CREB fusion–positive tumors. These trials should focus on its potential both as a monotherapy and in combination with other targeted agents or immunotherapies, aiming to improve patient outcomes, particularly in cases in which current treatment strategies offer limited benefit. Concurrently, advancements in molecular diagnostic technologies are broadening the scope for targeted therapies in cancer treatment. Inhibiting pathways such as interleukin-6/STAT3 have emerged as a promising therapeutic strategy,²⁷ while epigenetic subtyping offers a new approach for personalizing treatment.²⁸ These developments in molecular subtyping and targeted therapies are expected to refine the management of IMMT, leading to improved clinical outcomes and enhanced quality of life for patients.

Lessons

Resection, particularly GTR, remains the cornerstone of treatment for IMMTs. Patients with EWSR1-ATF1 fusion-positive IMMT, who are at higher risk of recurrence, can benefit from adjuvant radiotherapy to reduce this risk. By contrast, IMMTs with EWSR1-CREB1 fusions generally exhibit more stable biological behavior and often achieve favorable outcomes without the need for additional therapy. However, due to the rarity of IMMT, standardized adjuvant treatment protocols have not yet been established. Advances in molecular diagnostics are likely to drive progress in precise subtyping based on gene fusions, paving the way for personalized treatment approaches.

Despite the relatively high overall survival rate for IMMT, the heterogeneity in recurrence patterns and therapeutic responses underscores the need for further study. Current data are insufficient to provide definitive conclusions on long-term prognosis, but preliminary evidence indicates that EWSR1-ATF1 fusion positivity is associated with a higher recurrence risk. Future multicenter studies and long-term follow-up will be essential to refine diagnostic criteria and therapeutic strategies for this rare tumor.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Jin, Tian, Tang. Acquisition of data: Jin, Tian, D Wang, Huang. Analysis and interpretation of data: Jin, Li, Ding. Drafting the article: Jin, Ding. Critically revising the article: Yang, Li, Tang. Reviewed submitted version of manuscript: Yang, Tang. Approved the final version of the manuscript on behalf of all authors: Yang. Statistical analysis: D Wang, Huang. Administrative/technical/material support: Yang, R Wang. Study supervision: Yang, D Wang.

Correspondence

Kun Yang: Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu, China. yungkun@126.com.