Further evidence of EWSR1::GFI1B fusion in soft tissue angiofibroma: two new cases

In 2023, Suurmeijer et al. reported three cases of soft tissue angiofibroma harbouring the EWSR1::GFI1B gene fusion, proposing that this fusion may represent a novel molecular variant.1 In this report we present the clinicopathologic and molecular findings from two additional cases of soft tissue angiofibroma with the same EWSR1::GFI1B fusion, further reinforcing the existence of this molecular variant. Case 1: A 28-year-old male presented with dysphagia and a slow-growing neck mass. Ultrasound of the neck revealed a well-marginated, homogeneous, hypoechoic mass measuring 3.0 cm, located just left of the midline at the IIA/IIB neck level (Figure 1A). Doppler imaging showed no significant internal flow, and a computed tomography (CT) scan demonstrated a heterogeneous, well-defined mass at the level of the thyroid cartilage (Figure 1B), with no involvement of the thyroid or cervical lymph nodes. The clinical impression favoured an ectopic thyroid or thyroglossal duct remnant. The mass was excised, and, intraoperatively, it was found between the strap muscles, adhered to the hyoid bone, without invading the surrounding structures. Histologic sections revealed a well-circumscribed but unencapsulated neoplasm composed of bland spindle to ovoid cells with fine chromatin, inconspicuous nucleoli, and delicate eosinophilic cytoplasm, set within a collagenous stroma. Numerous thin-walled, branching blood vessels were distributed uniformly, with areas of perivascular hyalinization (Figure 1C–F). The lesional cells showed no immunoreactivity for CD34, desmin, SMA, SOX-10, S-100, cytokeratin AE1/AE3, EMA, GLUT-1, or MUC4. Whole-transcriptome sequencing (RNAseq) revealed an in-frame gene fusion involving the exon 7 of EWSR1 at the 5′ end (chr22:29683122, NM_005243) and exon 2 of GFI1B at the 3′ end (chr9:135862045, NM_001377304) (Figure 3A). Additional details about the sequencing methodology can be found in File S1. There is no evidence of clinical recurrence in a limited follow-up duration of 6 months. Case 2: A 24-year-old male with a history of Hodgkin's lymphoma, treated with chemoradiation, presented with a right lateral neck mass measuring 4 × 3 cm. CT imaging of the brain, neck, chest, and abdomen revealed no other abnormalities. A biopsy followed by surgical resection was performed. Histologic evaluation showed a poorly circumscribed lesion that infiltrated skeletal muscle fibres at the periphery. The lesion was composed of bland spindle cells, arranged in vague fascicles and a haphazard pattern, with minimal cytologic atypia, eosinophilic cytoplasm, and interspersed thin- and thick-walled blood vessels. A scant chronic inflammatory infiltrate and rare pseudolipoblasts (lesional cells containing intracytoplasmic mucin) were also present (Figure 2A–D). The neoplastic cells were positive for CD34 and focally for SMA, but negative for desmin, S100, MUC4, and EMA. RNAseq identified a gene fusion involving exon 7 of EWSR1 at the 5′ end (chr22: 29683123, NM_005243) with exon 3 of GFI1B at the 3′ end (chr9:135862669, NM_001377304) (Figure 3B), resulting in an in-frame fusion product. See the File S1 for methodology. There is no evidence of clinical recurrence within a limited follow-up duration of 1 year. Table 1 summarizes the clinicopathologic and molecular features of these two cases, along with the three previously reported cases of soft tissue angiofibroma with EWSR1::GFI1B gene fusion.1 All five cases involved male patients, with a mean age of 43 years (range: 24–78 years) and a mean tumour size of <3 cm (range: 2.2–4.0 cm). Notably, four of the five cases occurred in the neck and chest wall, contrasting with the lower extremity predilection of classic soft tissue angiofibroma.2-4 All cases demonstrated bland spindle to ovoid cell morphology, variable myxocollagenous stroma, and numerous small, branching blood vessels. Three cases had prominent to focal collagen bundles. In four out of five cases, the tumours exhibited infiltrative growth into the surrounding skeletal muscle or subcutaneous tissue. Of note, the vascular networks showed mild variation in size, with no hemangiopericytoma-like vasculature. Immunophenotypic profiling was largely nonspecific, with CD34 expression in two cases and focal expression of CK and SMA in one case each. None of the cases exhibited cytologic atypia, mitotic activity, or necrosis. Follow-up data, with a mean duration of 9 months, showed no evidence of disease, suggesting an indolent course. In summary, these two additional cases further support the existence of a novel molecular variant of soft tissue angiofibroma with EWSR1::GFI1B gene fusion. The tumours appear to show a predilection for the neck and chest wall regions and exhibit indolent behaviour in the short-term follow-up. Further studies with additional cases are needed to fully characterize this molecularly defined subtype. I. John designed the study and edited the article. A. Neyaz prepared the first draft. I. Giovannoni and J. Skaugen interpreted the molecular data. L. Lobo provided the radiologic interpretation. A. Mazzocca provided clinical data of case 2, S. Chiosea and R. Alaggio interpreted morphologic and immunohistochemical data, reviewed, and edited the study. No funding was received for this study by any author. No competing interest for any author. The data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.