Central nervous system embryonal tumor with BRD4-LEUTX gene fusion: A rare case

INTRODUCTION

The 2021 World Health Organization (WHO) classification introduced several molecularly defined subtypes, including cribriform neuroepithelial tumor, central nervous system (CNS) neuroblastoma, FOXR2-activated, and CNS tumor with BCOR internal tandem duplication.^[1] Integrating molecular findings in subtyping tumors holds great promise for advancing our knowledge in this field. However, novel molecular alterations in rare tumors continue to emerge, necessitating further characterization to refine diagnostic frameworks and treatment approaches.

One such recently identified alteration is the BRD4-LEUTX fusion, reported in a subset of embryonal CNS tumors.^[2] BRD4, a member of the bromodomain and extraterminal (BET) family, plays a critical role in chromatin remodeling and transcriptional activation, whereas LEUTX, a homeobox transcription factor, is involved in early embryonic development.^[3] The oncogenic role of this fusion remains unclear, and it has not yet been formally included in the WHO classification.

Here, we present a rare case of an embryonal CNS tumor with BRD4-LEUTX fusion in a 2-year-old girl, detailing its clinical presentation, histopathological features, immunoprofile, and molecular findings. Given the limited number of reported cases, this report contributes to the expanding literature and stresses the need for further research into its diagnostic criteria, prognostic implications, and potential targeted therapies.

CASE REPORT

A 2-year-old girl presented to the emergency department with progressive vomiting, right lower limb weakness, facial deviation, and squint, which had been worsening over two months. Initially, she was treated as a case of gastritis, but her symptoms persisted, leading to motor regression, right lower limb weakness, and intermittent outward deviation of the right eye.

A computed tomography scan revealed a large lateral ventricular mass (9.0 × 7.4 × 7.0 cm) on the left side, causing significant mass effect, rightward midline shift, and supratentorial hydrocephalus. In addition, hyperdense leptomeningeal lesions were identified, suggesting cerebrospinal fluid (CSF) seeding. Further magnetic resonance imaging evaluation confirmed a large lobulated lesion at the left posterior horn of the lateral ventricle, with extensive intracranial and spinal CSF dissemination, resulting in midline shift, midbrain compression, and active supratentorial hydrocephalus [Figure 1]. The radiological differential diagnosis included choroid plexus carcinoma, embryonal tumor with rhabdoid features, and supratentorial ependymoma.

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Figure 1:

Brain magnetic resonance imaging (a: Axial and b: Sagittal) T2 showing lobulated large mass with heterogenous signal intensity causing midline shift and hydrocephalus.

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The patient underwent tumor debulking, and frozen section examination revealed a small round blue cell tumor. Microscopic examination showed a densely cellular tumor arranged in vague lobules, separated by a delicate branching vascular network, with extensive calcifications and multiple areas of geographic necrosis [Figure 2]. The tumor cells have scant cytoplasm, a high nuclear-to-cytoplasmic ratio, hyperchromatic nuclei, and frequent mitotic figures with apoptotic bodies. Features of nuclear molding, grooves, and pseudoinclusions were also present [Figure 3].

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Figure 2:

Histological features of the tumor (low-power). (a) Tumor geographical necrosis (hematoxylin and eosin [H&E] stain, magnification ×20). (b) Extensive calcifications (H&E stain, magnification ×40). (c) Desmoplasia (H&E stain, magnification ×100). (d) Vague lobular growth pattern with delicate vasculature (H&E stain, magnification ×200).

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Figure 3:

Histological features of the tumor (high power). (a) Tumor cells with high nuclear: Cytoplasmic ratio and nuclear molding (hematoxylin and eosin [H&E] stain, magnification ×1000 oil). (b) Nuclei with frequent psudoinclusions (H&E stain, magnification ×1000 oil). (c) Apoptotic bodies and mitoses (H&E stain, magnification ×1000 oil). (d) Desmoplasia (H&E stain, magnification ×1000 oil).

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Immunohistochemistry studies demonstrated strong reactivity of the tumor cells toward Synaptophysin, CD56, NSE, Beta-Catenin, and S100, while EMA, SOX10, PAX8, BCL2, Chromogranin, GFAP, and OLIG2 were negative. INI-1 nuclear expression was retained, and P53 immunostaining displayed a wild-type pattern. The Ki-67 proliferative index was high (80%) [Figure 4]. Reticulin and Silver stains delineated desmoplasia.

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Figure 4:

Immunohistochemical features. Beta-catenin showed positive membranous expression. CD56 revealed positive cytoplasmic expression. GFAP illustrated entrapped astrocytes. INI1 was retained. Ki67 proliferative index was high (80%). NSE showed diffuse cytoplasmic expression. P53 was wild type. S100 revealed positive cytoplasmic and nuclear expression. Synaptophysin was positive. Magnification x400.

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Ultrastructural examination revealed primitive tumor cells with occasional rosette formations but no identifiable cell membrane junctional complexes or desmosomes. Occasional cells exhibited increased intracytoplasmic glycogen, along with numerous abnormal mitochondria (elongated, donut-shaped, and ring-shaped). Rare rectangular crystalline inclusions were also noted. The nuclei showed prominent molding, grooving, and pseudoinclusions. The calcifications took several types: (1) Amorphous and granular with lamination. (2) Crystalline star-shaped with lamination. (3) Crystalline star-shaped with no lamination [Figure 5].

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Figure 5:

Electron microscopic images. (a) Tumor cell rosettes. (b) Nuclear molding. (c) Nuclear grooves and pseudoinclusions. (d) Abundant cytoplasmic glycogen. (e) Abnormal mitochondria. (f) Crystalline inclusion (low-power). (g) Crystalline inclusion (high-power). (h) Filamentous material. (i) Collagen fibrils. (j) Laminated granular calcifications. (k) Laminated crystalline calcifications. (l) Star-shaped crystalline calcifications.

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Molecular studies confirmed that the tumor was microsatellite-stable and had a tumor mutational burden of 2 Muts/Mb. The detection of the BRD4-LEUTX fusion prompted a diagnosis of CNS embryonal tumor with BRD4-LEUTX gene fusion.

The patient was scheduled for a second debulking surgery and chemotherapy. However, she developed Gram-negative ventriculitis, necessitating antibiotic treatment. In addition, she experienced uncontrolled hypertension, requiring labetalol and amlodipine. The tumor progressed rapidly, leading to severe neurological deterioration, generalized cerebral dysfunction, and quadriplegia. The patient succumbed to the disease 3 months after the initial presentation.

DISCUSSION

Tumors harboring the BRD4-LEUTX gene fusion are exceptionally rare, with only a limited number of reported cases, as summarized in Table 1. Since its initial identification, nine cases have been documented in CNS embryonal tumors, with additional reports in soft-tissue sarcomas, such as epithelioid undifferentiated sarcoma of the orbit^[4] and alveolar rhabdomyosarcoma.^[5] Our case contributes to this growing body of literature, further characterizing the clinical course, histopathology, molecular profile, and ultrastructural characteristics of CNS embryonal tumors with BRD4-LEUTX fusion.

CNS embryonal tumors with BRD4 LEUTX fusion predominantly affect young children, typically under 4 years of age, and exhibit aggressive clinical behavior with a poor prognosis.^[2] Consistently, our patient, a 2-year-old girl, presented with a large intraventricular tumor and rapid disease progression. These tumors often demonstrate extensive CSF dissemination, resulting in the early neurological deterioration.

Histologically, these tumors exhibit small, round, blue cell morphology, high mitotic activity, nuclear molding, and apoptotic bodies, consistent with our case.^[2] The immunohistochemical profile is typically positive for Synaptophysin, CD56, NSE, Beta-Catenin, and S100, with retained INI-1 expression, as observed in previous cases.^[3] Notably, our case introduces a new finding to the existing literature, as ultrastructural examination revealed extensive calcifications and crystalline inclusions, features that have not been previously described in this tumor subtype.

The BRD4-LEUTX fusion is a novel oncogenic driver, and its precise molecular mechanisms remain poorly understood.^[2] BRD4, a BET family protein, plays a key role in transcriptional regulation, while LEUTX, a homeobox transcription factor, is primarily involved in embryonic genome activation.^[4] The fusion likely leads to aberrant activation of embryonic transcriptional programs, driving oncogenesis.^[5] The presence of this fusion in pediatric sarcomas further supports its potential oncogenic significance beyond CNS tumors.^[4]

Given the role of BRD4, there is increasing interest in targeting BET proteins with epigenetic therapies such as BET inhibitors.^[6] These inhibitors have demonstrated preclinical efficacy in BRD4-driven tumors, suggesting a potential therapeutic avenue for BRD4-LEUTX tumors.^[7] Considering these findings and the aggressive disease course with poor response to conventional therapy, further preclinical and clinical investigations are needed to assess their effectiveness in CNS embryonal tumors.^[2]

Despite aggressive surgical intervention and chemotherapy, our patient experienced rapid tumor progression, reinforcing the poor prognosis associated with CNS embryonal tumors harboring BRD4-LEUTX fusion.^[2] This stresses the need for improved molecular classification and targeted therapeutic strategies.

CONCLUSION

This case adds to the limited literature on CNS embryonal tumors with BRD4-LEUTX fusion, highlighting their aggressive nature and dismal clinical outcomes. Given the rarity of this entity, continued case reporting, molecular characterization, and therapeutic exploration are essential for improving diagnostic accuracy and refining treatment approaches. Future studies should focus on targeted therapy development to enhance survival outcomes for patients with this rare and aggressive tumor subtype.