EWSR1::BEND2 fusion sarcoma of the urinary bladder – a case report and review of literature

Authors

Vili Halava

Jenni Tuominen

Paula Lindholm

Timo Kyyrönen

Markku Kallajoki

Katri Orte

Doi

10.1186/s13000-025-01721-3

PMID: 28199314 · DOI: 10.1186/s13000-025-01721-3 · Journal: Diagnostic Pathology (2025)

TL;DR

Halava et al. report a single-patient case of a high-grade undifferentiated small round cell sarcoma of the urinary bladder in a previously healthy 28-year-old male, harbouring an extremely rare in-frame EWSR1::BEND2 fusion (EWSR1 exon 10 to BEND2 exon 2). The tumour was initially diagnosed as extraskeletal Ewing sarcoma based on CD99 positivity and FISH-detected EWSR1 rearrangement, and was treated on the ISG/SSG IV Ewing protocol followed by docetaxel/gemcitabine after disease progression and renal toxicity. RNA sequencing and DNA methylation profiling — performed later as part of a validation cohort — revealed the EWSR1::BEND2 fusion and a copy-number profile showing partial loss of 1q and 10q including PTEN. Methylation profile did not match any sarcoma classifier subclass; the brain-tumor classifier suggested low-confidence similarity to MN1::BEND2-rearranged astroblastoma. The patient died of disease 26 months after diagnosis.

Cohort & data

Key findings

  • An in-frame fusion transcript joining EWSR1 exon 10 (NM_005243.4, MANE Select) to BEND2 exon 2 (NM_153346.5, MANE Select) was detected by RNA-seq and confirmed by Sanger sequencing in a urinary-bladder small round cell sarcoma PMID:28199314.
  • Histology: small blue round cell tumour, perivascular pseudorosettes, mitotic rate 15/10 HPF, Ki-67 ~70%, focal necrosis. CD99 diffusely membranous positive; EMA positive; vimentin and low-MW cytokeratin (Cam 5.2) showed weak golgi-like perinuclear staining; INI1 (SMARCB1) and SMARCA4 retained; lymphoid, germ cell, neuroendocrine and melanocytic markers negative PMID:28199314.
  • EWSR1 break-apart FISH was positive (translocation in the majority of cells), but did not identify the fusion partner; the partner was only resolved by RNA-seq, illustrating the limited specificity of FISH for EWSR1 rearrangements PMID:28199314.
  • The tumour’s DNA methylation profile did not classify with the sarcoma classifier (Koelsche et al. v13). On the brain-tumor classifier, it suggested similarity to MN1::BEND2-rearranged astroblastoma with a low prediction score of 0.364 PMID:28199314.
  • Copy-number profile derived from methylation array showed partial loss of chromosome arms 1q and 10q, including loss of the tumor suppressor PTEN PMID:28199314.
  • Treatment course: doxorubicin neoadjuvant monotherapy followed by ISG/SSG IV protocol (vincristine, doxorubicin, ifosfamide, etoposide); intravesical tumour disappeared after 2 months but pelvic and lung disease did not respond. Bladder/prostate radiotherapy 50 Gy at month 4. Switched to docetaxel + gemcitabine (16 cycles) due to progression and nephrotoxicity; disease was approximately stable on this regimen. Patient died at 26 months post-diagnosis PMID:28199314.
  • Literature review: outside the central nervous system, EWSR1::BEND2 fusions have been reported in salivary gland carcinoma, tracheal adenocarcinoma, a pancreatic neuroendocrine tumor, low-grade sinonasal sarcoma, and high-grade undifferentiated bone sarcomas; the bladder location reported here is novel PMID:28199314.

Genes & alterations

  • EWSR1 — 5’ fusion partner; in-frame fusion of exon 10 to BEND2 exon 2; detected by both break-apart FISH and RNA-seq. The N-terminal transcription activation domain of EWSR1 is contributed to the fusion protein PMID:28199314.
  • BEND2 — 3’ fusion partner; contributes its C-terminal BEN domain to the fusion. Same fusion is described in a subset of astroblastoma (ASTB) (typically replacing MN1 alterations), but the EWSR1 breakpoint here differs from those reported in CNS cases PMID:28199314.
  • PTEN — partial loss via 10q deletion observed on methylation-derived copy-number profile; flagged by authors as potentially actionable (PI3K/AKT/mTOR pathway, possible mTOR-inhibitor or PARP-inhibitor sensitivity) although not pursued therapeutically in this patient PMID:28199314.
  • MN1 — discussed as the canonical fusion partner in astroblastoma; MN1::BEND2 fusions characterise an epigenetic subtype of astroblastoma to which this tumour showed weak methylation similarity PMID:28199314.
  • FLI1 — discussed as the most common ETS-family partner in canonical Ewing sarcoma (EWSR1::FLI1); not present in this case, which falls in the EWSR1-non-ETS group PMID:28199314.
  • NFATC2, PATZ1, POU2AF3 — discussed as other characterised EWSR1-non-ETS fusion partners in WHO 2020’s “round cell sarcoma with EWSR1-non-ETS fusions” category, alongside EWSR1::BEND2 PMID:28199314.
  • CIC, BCOR — discussed as defining alterations of related undifferentiated small round cell sarcoma entities (CIC-rearranged sarcoma; BCOR-altered sarcoma) PMID:28199314.
  • FUS — discussed as the other FET-family gene that can substitute for EWSR1 in EWSR1-non-ETS-equivalent fusions PMID:28199314.
  • SMARCB1 (INI1) and SMARCA4 — protein expression retained on IHC, ruling out SWI/SNF-deficient differential diagnoses PMID:28199314.

Clinical implications

  • This is the first reported EWSR1::BEND2 fusion sarcoma of the urinary bladder, expanding the anatomical spectrum of EWSR1::BEND2 neoplasms beyond CNS (astroblastoma), salivary gland, trachea, pancreas, sinonasal cavity and bone PMID:28199314.
  • Per ESMO guidelines, an Ewing-sarcoma–like chemotherapy approach is reasonable for these ultra-rare EWSR1-non-ETS fusion sarcomas in the absence of dedicated trials; in this patient the ISG/SSG IV protocol controlled the primary intravesical disease but failed to control pelvic and pulmonary metastases PMID:28199314.
  • Authors argue that broad genomic testing in undifferentiated small round cell sarcomas can surface co-occurring actionable alterations even when the defining fusion is not directly targetable; here, PTEN loss was identified as a potential biomarker for mTOR or PARP inhibition (citing supporting literature) but was not pursued in this patient PMID:28199314.
  • The case underscores that EWSR1 break-apart FISH alone is insufficient to diagnose Ewing sarcoma — EWSR1 rearrangements are now found in tumours of widely varying morphology, behaviour, and lineage; partner identification by RNA-seq is required to refine diagnosis and prognosis PMID:28199314.

Limitations & open questions

  • N = 1 case report: clinical behaviour, response patterns, and the value of any specific therapeutic strategy for EWSR1::BEND2 bladder sarcoma cannot be generalised PMID:28199314.
  • Methylation classifier prediction score for astroblastoma (MN1-rearranged) was low (0.364), and no sarcoma classifier match was obtained — the epigenetic identity of this tumour entity remains unresolved PMID:28199314.
  • The EWSR1 breakpoint in this case (exon 10) differs from those reported in MN1::BEND2 / EWSR1::BEND2 astroblastomas, raising the question of whether EWSR1::BEND2 sarcomas form a distinct molecular subgroup separate from CNS cases PMID:28199314.
  • Authors flag the broader open question of how WHO classification should evolve to accommodate the proliferating list of EWSR1-non-ETS fusion partners (BEND2, NFATC2, PATZ1, POU2AF3, etc.) and whether site/morphology should split or merge these entities PMID:28199314.
  • PTEN-loss-directed therapy (mTOR or PARP inhibition) was discussed but not administered, leaving its clinical utility in this context untested PMID:28199314.

Citations from this paper used in the wiki

  • “Here, we describe a case of EWSR1::BEND2 fusion sarcoma of the bladder in a previously healthy male.” (p. 1)
  • “An in-frame fusion transcript with sequence from exon 10 of EWSR1 gene (NM_005243.4, MANE Select transcript) attached to sequence from exon 2 of BEND2 gene (NM_153346.5, MANE Select transcript) was observed.” (p. 3)
  • “The methylation profile of the tumor did not classify with the sarcoma classifier … but the brain tumor classifier suggested similarity to MN1::BEND2 rearranged astroblastoma although with low prediction score (0.364).” (p. 3)
  • “The copy number profile showed partial loss of chromosome areas 1q and 10q resulting in e.g. loss of tumor suppressor gene PTEN.” (p. 3)
  • “After Ewing sarcoma diagnosis, doxorubicin neoadjuvant monotherapy was changed to ISG/SSG IV … consisting of vincristine, doxorubicin, ifosfamide and etoposide …” (p. 3)
  • “ISG/SSG IV protocol was changed to combined docetaxel and gemcitabine … The patient received 16 cycles of docetaxel-gemcitabine in total.” (p. 3)
  • “He died of the disease 26 months after the diagnosis at the age of 30 years 8 months.” (p. 4)
  • “PTEN loss may affect the efficacy of immune-oncological treatments but there is evidence that patients with defective PTEN might benefit from mTOR inhibitors or PARP inhibitors.” (p. 6)
  • “According to ESMO Guidelines, ES-like approach has usually been chosen for treatment of these new entities.” (p. 6)

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