Undifferentiated sarcoma of bone with a round to epithelioid cell phenotype harboring a novel <scp><i>EWSR1</i>‐<i>SSX2</i></scp> fusion identified by <scp>RNA</scp>‐based next‐generation sequencing

Undifferentiated mesenchymal neoplasms can be morphologically subclassified based on cell shape; epithelioid tumors may be diagnostically challenging, particularly since they can show morphologic and immunohistochemical overlap with epithelial neoplasms. Following the recent report of an NR1D1::MAML1 gene fusion in an undifferentiated pediatric neoplasm, we performed a retrospective archival review and identified four additional cases of undifferentiated mesenchymal neoplasms with NR1D1‐rearrangement. All four tumors occurred in adult women. The tumors involved superficial and/or deep soft tissues of the extremities or abdomen. Morphologically, they showed a spectrum of overlapping features. In addition to epithelioid cells, two cases also had a prominent spindle cell component. Two cases also had admixed polygonal cells containing prominent cytoplasmic vacuoles with amorphous debris. The immunophenotype was nonspecific but all cases had at least focal keratin expression; this was extensive in two tumors. Targeted RNA‐sequencing revealed two cases each with NR1D1::MAML1 and NR1D1::MAML2 gene fusions. One patient developed lung and liver metastases, and one patient required amputation due to multifocal disease and underlying bone involvement. This study confirms undifferentiated NR1D1‐rearranged sarcoma represents a distinct mesenchymal neoplasm with an epithelioid morphology and potential for aggressive behavior. Further, we offer new insight into the spectrum of clinical, morphologic, immunohistochemical, and molecular findings possible in these rare neoplasms. An awareness of this entity is especially important given the potential for misclassification as a carcinoma.

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Expanding the spectrum of mesenchymal neoplasms with NR1D1‐rearrangement

Lacambra

Antonescu

Chit

et al. 2022

“…However, the presence of an EWSR1 gene rearrangement by FISH ruled out this possibility. Very recently, a case of undifferentiated sarcoma of bone harboring EWSR1::SSX2 fusion and two cases of poorly differentiated sarcomas with round to epithelioid cell morphology both harboring EWSR1 :: SSX1 fusion were described by Cordier et al 7 and Antonescu et al, 6 respectively. The first one consisted of an undifferentiated tumor composed of round to epithelioid cells arranged in solid sheets, with scant cytoplasm, vesicular nuclei, and prominent nucleoli; areas of spindle cells with more pleomorphism were identified.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, due to the ever‐expanding application of targeted RNA sequencing in clinical practice, including on archival material and small biopsies, the pace of molecular discoveries in the past few years has been extraordinary, with novel gene fusions being reported on a monthly basis. Thus, new groups of undifferentiated round and spindle cell sarcomas have emerged, mostly characterized by non‐canonical EWSR1 ‐related fusions, outside the Ewing or Ewing‐like spectrum, such as EWSR1::KLF15 4,5 and EWSR1::SSX1 6 in soft tissue or EWSR1::SSX2 7 in bone. The current study reports on a highly aggressive undifferentiated sarcoma arising in a young adult harboring a novel EWSR1::SSX3 fusion gene, highlighting the diagnostic value of RNA‐sequencing in identifying novel fusions to improve further the existing molecular classification.…”

Section: Introductionmentioning

confidence: 99%

Expanding the molecular landscape of undifferentiated sarcomas of bone with a novel EWSR1‐SSX3 gene fusion

Fumagalli,

Orellana,

Ferré

et al. 2023

Undifferentiated sarcomas characterized by a primitive monomorphic round to spindle cell phenotype and often non‐specific immunoprofile remain difficult to subclassify outside molecular analysis. The increased application of RNA sequencing in clinical practice led to significant advances and discoveries of novel gene fusions that furthered our understanding and refined classification of otherwise undifferentiated neoplasms. In this study, we report an undifferentiated round to spindle cell sarcoma arising in the femur of a 34‐year‐old female. The round to spindle tumor cells were arranged in short fascicles, with focal rosette formation, within a hyalinized stroma. The tumor immunoprofile included diffuse reactivity for CD99, SATB2, and TLE1 and patchy positivity for Cyclin D1, Keratin AE1/AE3, synaptophysin, and chromogranin. Other markers, such as EMA, SMA, desmin, S100, ERG, and WT1, were negative. Fluorescence in situ hybridization analysis for EWSR1 gene alterations showed a break‐apart signal and targeted RNA sequencing revealed an EWSR1::SSX3 gene fusion. The patient received neoadjuvant chemotherapy followed by surgery and subsequently relapsed in less than a year with lung metastasis. Larger series are needed to determine if this fusion defines a novel subset of undifferentiated tumors or represents a genomic variant of already existing primitive round cell sarcoma categories, such as Ewing sarcoma or synovial sarcoma.

“…This is especially relevant in the diagnostic process of sarcomas characterized by fusions involving the so‐called FET‐genes ( FUS , EWSR1 , and TAF15 ), as the different subtypes require different treatment strategies. 17 , 18 , 19 …”

Section: Discussionmentioning

confidence: 99%

A cryptic EWSR1::DDIT3 fusion in myxoid liposarcoma: Potential pitfalls with FISH and cytogenetics

Ibstedt

Mattos

Koster

et al. 2022

Myxoid liposarcoma (MLS) is molecularly characterized by fusions involving the DDIT3 gene in chromosome band 12q13; the fusion partner is FUS in band 16p11 in 90-95% of the cases and EWSR1 in band 22q12 in the remaining 5-10%.Hence, molecular studies, often fluorescence in situ hybridization (FISH) for DDIT3 rearrangement, are useful for establishing a correct diagnosis. Although all MLS tumors should have DDIT3 fusions, it is important to be aware of reasons for potential false-negative results. We here present a case of MLS that was negative for FISH for DDIT3, that showed an unexpected t(11;22) at G-banding, but that displayed a characteristic EWSR1::DDIT3 fusion at RNA-sequencing. The results suggest that neoplasia-associated fusions that, due to the transcriptional orientations of the two genes involved, cannot arise through only two double-strand breaks are more likely to be associated with negative FISH-findings and unexpected karyotypes.