Undifferentiated Round Cell Sarcomas Research Articles

Ganglioneuronal Differentiation in Ewings Sarcoma of the Chest Wall (Askin Tumour): An Uncommon Post-Chemotherapy Change

Ewing sarcoma is classified under undifferentiated small round cell sarcomas of bone and soft tissue. Such tumours arising in the chest wall were previously called Askin’s tumour, however this terminology is not preferred at present. These tumours classically have a small round cell morphology and fusion of FET family of genes (usually EWSR1) with a member of the ETS family of transcription factors. Rare cases of Ewing sarcoma are found to have extensive neural differentiation with ganglion cells and neuropil at diagnosis as well as following chemotherapy. We report a 12 year old boy who presented with a large mass in the right hemi-thorax, which was diagnosed as Ewing sarcoma with EWSR1 translocation by FISH. However, following four cycles of chemotherapy (Vincristine, Doxorubicin, Cyclophosphamide alternating with ifosphamide and etoposide), the resection specimen showed predominantly neural differentiation mimicking a ganglioneuroma with only small areas of small round cell component. EWSR1 translocation was also demonstrated in the resection specimen. After a period of nine months, the child presented with recurrence at the same site and was treated with Irinotecan, cyclophosphamide with topotecan and temozolamide giving excellent clinical response. In this paper, we emphasize the rare occurrence of extensive neural differentiation in Ewing sarcoma and the need to revisit the upfront chemotherapy protocols for patients who exhibit this rare phenomenon

Patterns of care and outcome of CIC-rearranged sarcoma patients: A nationwide study of the French sarcoma group.

CIC-rearranged sarcomas (CIC-RS) represent the most frequent subset of "Ewing-like" undifferentiated small round cell sarcomas. These tumors tend to be more aggressive than Ewing sarcomas. Moreover, treatment strategy can differ according to teams. The primary aim of this retrospective study was to describe the characteristics, treatments, and outcome for patients with CIC-RS included in the French NETSARC+ database. Pediatric and adult patients from 13 French centers with a diagnosis of CIC-RS were registered from October 2008 to March 2021. Patients and tumors characteristics were collected from the national network NETSARC+ database (http://netsarc.sarcomabcb.org). CIC-RS diagnosis was pathologically and molecularly confirmed with a central review by expert pathologists. Two groups of patients were studied: those treated as classical Ewing sarcomas (cohort EwS) and those treated as high-grade soft tissue sarcomas (cohort STS) according to ESMO and/or EpSSG guidelines. Survival was calculated using the Kaplan-Meier method and the log-rank test was used to compare survival. Among 79 patients, the male/female sex ratio was 0.7 and the median age at diagnosis was 27 years (range 2-87). With a median follow-up of 37 months, 39 patients died of the disease. Median overall survival from diagnosis was 18 months, with no significant difference between both cohorts (p=0.9). Nevertheless, when focusing on patients with metastatic disease at diagnosis (N=21), all patients from cohort STS died of disease while some patients from cohort EwS were still alive and in complete remission. FSG experience confirms the aggressive clinical course of CDS patients regardless of chemotherapy regimen.

Sarcoma with BCOR gene alterations (BCOR-ITD) of the L3 vertebra in an 8-year-old boy

In the 2020 World Health Organization classification, for the first time, three new groups of tumors were formalized, initially isolated from the group of undifferentiated round cell sarcomas, the so-called Ewing-like sarcomas, namely sarcoma with BCOR genetic alterations, CIC-rearranged sarcoma and sarcomas with EWSR1 gene rearrangement with atypical (non-ETS family) partner genes. This review will focus on sarcoma with BCOR genetic alterations, which will be illustrated by one of our clinical case, characterized by relatively typical features, both in terms of morphological presentation and immunophenotype, and in terms of biological behavior and response to tumor therapy. The patient's parents gave their consent to the use of their child's data, including photographs, for research purposes and in publications.

Small round cell sarcomas.

Undifferentiated small round cell sarcomas (SRCSs) of bone and soft tissue comprise a heterogeneous group of highly aggressive tumours associated with a poor prognosis, especially in metastatic disease. SRCS entities mainly occur in the third decade of life and can exhibit striking disparities regarding preferentially affected sex and tumour localization. SRCSs comprise new entities defined by specific genetic abnormalities, namely EWSR1-non-ETS fusions, CIC-rearrangements or BCOR genetic alterations, as well as EWSR1-ETS fusions in the prototypic SRCS Ewing sarcoma. These gene fusions mainly encode aberrant oncogenic transcription factors that massively rewire the transcriptome and epigenome of the as yet unknown cell or cells of origin. Additional mutations or copy number variants are rare at diagnosis and, depending on the tumour entity, may involve TP53, CDKN2A and others. Histologically, these lesions consist of small round cells expressing variable levels of CD99 and specific marker proteins, including cyclin B3, ETV4, WT1, NKX3-1 and aggrecan, depending on the entity. Besides locoregional treatment that should follow standard protocols for sarcoma management, (neo)adjuvant treatment is as yet ill-defined but generally follows that of Ewing sarcoma and is associated with adverse effects that might compromise quality of life. Emerging studies on the molecular mechanisms of SRCSs and the development of genetically engineered animal models hold promise for improvements in early detection, disease monitoring, treatment-related toxicity, overall survival and quality of life.

MRNA Capture Sequencing and RT-qPCR for the Detection of Pathognomonic, Novel, and Secondary Fusion Transcripts in FFPE Tissue: A Sarcoma Showcase.

We assess the performance of mRNA capture sequencing to identify fusion transcripts in FFPE tissue of different sarcoma types, followed by RT-qPCR confirmation. To validate our workflow, six positive control tumors with a specific chromosomal rearrangement were analyzed using the TruSight RNA Pan-Cancer Panel. Fusion transcript calling by FusionCatcher confirmed these aberrations and enabled the identification of both fusion gene partners and breakpoints. Next, whole-transcriptome TruSeq RNA Exome sequencing was applied to 17 fusion gene-negative alveolar rhabdomyosarcoma (ARMS) or undifferentiated round cell sarcoma (URCS) tumors, for whom fluorescence in situ hybridization (FISH) did not identify the classical pathognomonic rearrangements. For six patients, a pathognomonic fusion transcript was readily detected, i.e., PAX3-FOXO1 in two ARMS patients, and EWSR1-FLI1, EWSR1-ERG, or EWSR1-NFATC2 in four URCS patients. For the 11 remaining patients, 11 newly identified fusion transcripts were confirmed by RT-qPCR, including COPS3-TOM1L2, NCOA1-DTNB, WWTR1-LINC01986, PLAA-MOB3B, AP1B1-CHEK2, and BRD4-LEUTX fusion transcripts in ARMS patients. Additionally, recurrently detected secondary fusion transcripts in patients diagnosed with EWSR1-NFATC2-positive sarcoma were confirmed (COPS4-TBC1D9, PICALM-SYTL2, SMG6-VPS53, and UBE2F-ALS2). In conclusion, this study shows that mRNA capture sequencing enhances the detection rate of pathognomonic fusions and enables the identification of novel and secondary fusion transcripts in sarcomas.

Retrospective study on the efficacy and safety of low dose apatinib in reversing chemotherapy resistance in sarcoma

Objective: To explore whether apatinib can reverse the chemotherapy resistance of patients with advanced sarcoma. Methods: The clinical data of advanced sarcoma patients after chemotherapy who received the original chemotherapy regimen combined with low-dose apatinib in Cancer Center of Union Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology from May 2018 to November 2021 were collected retrospectively to evaluate the efficacy and safety of this regimen. The primary end point was progression-free survival (PFS), and the secondary end points were objective response rate (ORR), disease control rate (DCR), overall survival (OS) and adverse events (AE). The patients were grouped according to the diagnosis: osteosarcoma, soft tissue sarcoma and undifferentiated small round cell sarcoma. And the benefits of combination treatment was investigated with the stratified analysis of best outcome of combined therapy, lines of chemotherapy received, best response and PFS of original chemotherapy. Results: A total of 30 patients were included in this study, including 20 males and 10 females. The mean age was (25.6±14.7) years. There were 9 cases of osteosarcoma, 11 cases of soft tissue sarcoma and 10 cases of undifferentiated small round cell sarcoma. No patient achieved complete response, 8 patients (26.7%) achieved partial response, 19 patients (63.3%) achieved disease stability, the ORR was 26.7%(8/30), and the DCR was 90.0%(27/30). The median PFS and OS were 4.1 and 13.1 months respectively. Among the three different subtypes of sarcoma, the ORR of osteosarcoma was 44.4% (4/9), the median PFS was 4.1 months, and the median OS was not yet achieved; the ORR of undifferentiated small round cell sarcoma was 40% (4/10), the median PFS was 6.4 months, and the median OS was 10.9 months; No response was observed in soft tissue sarcoma, and the median PFS and median OS was 3.5 and 7.3 months respectively. Patients who achieved objective response had better PFS than patients with stable disease (12.8 vs 3.8 months, P=0.015), and patients with PFS≥ 6 months of original chemotherapy had better PFS benefits (12.7 vs 2.7 months, P<0.001). However, the number of original chemotherapy lines and the best response of original chemotherapy had no significant effect on the PFS of this combination regimen. In terms of safety, the related toxicity of apatinib was no more than grade 2, and the grade 4 chemotherapy-related adverse reactions was mainly hematological toxicity, of which 2 patients interrupted treatment because of febrile neutropenia. Conclusion: Low dose apatinib is effective in reversing chemotherapy resistance of osteosarcoma and undifferentiated small round cell sarcoma with acceptable adverse reactions.

The 2020 World Health Organization classification of bone tumors: what radiologists should know.

Improved understanding of tumor biology through molecular alteration and genetic advances has resulted in a number of major changes in the 2020 World Health Organization's (WHO) classification of bone tumors. These changes include the reclassification of the existing tumors and the introduction of several new entities. A new chapter on undifferentiated small round cell sarcomas of bone and soft tissue was added to classify Ewing sarcoma and the family of Ewing-like sarcomas, which share similar histologies but different molecular and clinical behaviors. Knowledge of the current classification of bone tumors is essential to ensure the appropriate recognition of the inherent biological potential of individual osseous lesions for optimal treatment, follow-up, and overall outcome. This article reviews the major changes to the 2020 WHO's classification of primary bone tumors and the pertinent imaging of selected tumors to highlight these changes.

CIC-DUX4 sarcomas.

CIC-DUX4 sarcoma (CDS) is a high-grade undifferentiated round cells sarcoma that belongs to the undifferentiated round cell sarcomas family. It represents less than one percent of sarcomas, defining a rarest among rare malignancies. It affects young adults, displaying soft tissue mass. Considered very aggressive, a high proportion of cases display an advanced disease with lung metastasis at diagnosis. Here we discuss recent progress in molecular characterization of CDS, the main tracks of CDS biology and the current and future prospects of therapeutic approaches. CDS is characterized by a specific oncogenic translocation CIC::DUX4 that induce ETV4 overexpression. Patients with CDS show an aggressive clinical course and have a significantly unfavorable outcome compared to Ewing sarcoma. As of today, there is a lack of consensus on whether they should be treated with an Ewing-like approach, as currently done by most sites, or regarded as high-grade soft tissue sarcoma (STS). Anyway, when feasible, combination regimens including anthracycline and alkylating agents should be favored and patients should not benefit from a therapeutic de-escalation. Overall, registration within clinical trials and prospective registries is recommended. Overall, CDS showed a poor prognosis regardless of the patterns of treatment that warrant biological studies to better understand the disease.

ETMR-03. Intra- and extra-cranial BCOR-ITD tumours are separate entities within the BCOR-rearranged family

BCOR-ITD tumours form an emerging family of aggressive entities with an internal tandem duplication (ITD) in the last exon of the BCOR gene. The family includes cerebral tumours, termed central nervous system BCOR-ITD (CNS BCOR-ITD), and sarcomatous types described in the kidney as clear cell sarcoma of the kidney (CCSK), in the endometrium as high-grade endometrial stromal sarcoma (HG-ESS), in bone, and in soft tissue as undifferentiated round cell sarcoma (URCS) or primitive myxoid mesenchymal tumour of infancy (PMMTI). Based on a series of 33 retrospective cases, including 10 CNS BCOR-ITD and 23 BCOR-ITD sarcomas, we interrogated the homogeneity of the entity regarding clinical, radiological and histopathological findings, and molecular signatures. Whole transcriptomic sequencing and DNA methylation profiling were used for unsupervised clustering. Histopathological review revealed marked differences between CNS BCOR-ITD and BCOR-ITD sarcomas. These two groups were consistently segregated by unsupervised clustering of expression (n=22) and DNA methylation (n=21) data. Proximity between the two groups may result from common somatic changes within key pathways directly related to the novel activity of the ITD itself. Conversely, comparison of gene signatures with single-cell RNAseq atlases suggests that the distinction between BCOR-ITD sarcomas and CNS BCOR-ITD may result from differences in cells of origin.

Prevalence of ultra-rare undifferentiated round cells sarcoma of bone and soft tissue after genomic classification.

11559 Background: Over the last decade, the category of undifferentiated round cell sarcomas (URCS), defined by the absence of Ewing sarcoma-associated translocations, has emerged. Aim of this study was to assess prevalence of each entity and outcome after genomic classification. Methods: Ewing sarcoma and other URCS diagnosed between 1920 and 2020 were reviewed. All URCS with available material were analyzed with FISH, RT-qPCR and/or Archer FusionPlex Sarcoma Panel. Demographic and treatment were collected. Survival was analyzed in patients with available follow-up. Results: 1995 cases identified, 20 cases lacked material for further genetic analysis and were excluded. 1975 cases were classified as follows: 1925 Ewing sarcomas (97.47%), 25 CIC-rearranged sarcomas (1.27%), 16 BCOR-CCNB3 rearranged sarcomas (0.81%), 2 EWSR1-NFATC2 sarcoma (0.1%), one each as CIC-LEUTX and FUS-NFATC2 rearranged sarcoma (0.05% each), and 5 as unclassified URCS (0.25%). A different presentation according to tumor type was shown in 43/50 ultra-rare tumors (Table). Forty-one/50 cases had available follow-up: 20/41 patients underwent surgery, 14/41 surgery+radiotherapy, 6 radiotherapy only, and no local treatment for 1 patient. Chemotherapy was administrated to 36/41 patients (Ewing sarcoma drugs in 16/22 CIC-DUX-4 and 8/11 BCOR-CCNB3; osteosarcoma drugs in 2/11 BCOR-CCNB3, and doxorubicin/ifosfamide in 2/22 CIC-DUX4 and 2/5 URCS; not specified in 6 cases). The 3-years overall survival (OS) was 32.7%f for CIC-rearranged sarcomas (75% in localize disease, 7,7% for the advanced disease, p 0.0084), 81.8% for BCOR-CCNB3 sarcomas (87.5% localized, 66.7% advanced; p 0.0734), and 60% for URCS (p 0.057). 1 patient with CIC-LEUTX sarcoma presenting with metastases died 13 months from diagnosis, 1 patient with FUS-NFATC2 and 1 with EWSR1-NFATC2 rearrenged sarcomas were alive without disease at 8 and 5 years from onset. Conclusions: Prevalence of URCS characterized by a combination of morphologic observation ad molecular techniques is provided. The majority of the cases underwent surgery or surgery combined with radiotherapy, and Ewing-like chemotherapy. The survival difference among different entities underscores the need of accurate subclassification of round cell sarcomas. Novel drugs for CIC-DUX-4 sarcomas presenting with metastases are needed. [Table: see text]

Molecular features of undifferentiated sarcoma of soft tissue and carcinoma.

e23519 Background: Both undifferentiated sarcoma of soft tissue and undifferentiated carcinomas can arise in multiple tissue and are with an aggressive clinical course. While undifferentiated sarcomas that remain a diagnosis of exclusion and show extreme genomic complexity, less is known about undifferentiated carcinoma. Methods: Sixty-two patients diagnosed as undifferentiated sarcoma (n = 36, 10 bone/limbs, 9 abdomen, 9 pelvis, and 8 chest/intrathoracic) or carcinoma (n = 26, excluding undifferentiated carcinoma of nasopharynx and thyroid, 15 chest/intrathoracic, 8 abdomen, and 3 pelvis) were recruited in the study. Mutational analysis was performed by next-generation sequencing of 1021 tumor related genes, which enabled analysis of TMB and MSI as well. PD-L1 expression data was available in 24 patients. Results: Fifty-eight patients (93.5%, 58/62) had at least 1 mutation identified and 542 SNV, 115 CNV and 5 fusions were identified in total in the 62 patients. The top 5 mutant genes were TP53 (56.5%, 35/62), TERT (11.3 %, 7/62), SMARCA4 (9.7%, 6/62), LRP1B (9.7%, 6/62), and MLL2 (9.7%, 6/62). Interestingly, mutation in TP53 was more common in undifferentiated carcinoma (73.08%, 19/26) than sarcoma (44.44%, 16/36, p = 0.0377). Two ERBB2 CNV and 1 KIF5B-RET fusion were identified in 2 gastric carcinoma and 1 lung large cell carcinoma. However, no carcinoma but 2 sarcoma (1 polymorphic undifferentiated sarcoma in the limb and 1 undifferentiated small round cell sarcoma in the lung) showed MSI-H, with TMB as high as 22.08 and 65.28 respectively, while the median TMB was 3.84 mutations/Mb. Among the 24 patients with PD-L1 data, 16 were &gt; 1%, and 5 were &gt; 50%, with no significant difference between undifferentiated carcinoma and sarcoma. Conclusions: In spite of the genome complexity in undifferentiated sarcoma of soft tissue and carcinoma, there was limited actionable mutations in these two aggressive tumors. However, immunotherapy should be considered since over half of these patients were PD-L1 positive and nearly a quarter of them had high PD-L1 expression.

BCOR-CCNB3 sarcoma with concurrent RNF213-SLC26A11 gene fusion: a rare sarcoma with altered histopathological features after chemotherapy

BackgroundChemotherapy is a common approach for cancer treatment, but intrinsic genetic mutations in different individuals may cause different responses to chemotherapy, resulting in unique histopathological changes. The genetic mutation along with the distinct histopathological features may indicate new tumor entities. BCOR-CCNB3 sarcomas is a kind of Ewing-like sarcomas (ELS) occurring mostly in bone and soft tissues. No gene fusion other than BCOR-CCNB3 has been found in this type of tumor.Case presentationWe herein report a case of 17-year-old male patient, presented with a mass on his left shoulder that was diagnosed as undifferentiated small round cell sarcoma according to core biopsy. The patient received 5 courses of preoperational chemotherapy, and the tumor was resected and analyzed. Primitive small round cells and larger myoid cells in the resected tumor tissue but not in biopsy were observed, and arterioles stenosis and occlusion were also detected, indicating a dramatic change of histopathological features of this tumor. In addition, the immunohistochemical results showed the altered staining patterns of BCOR, bcl2, CyclinD1, TLE1, AR, SMA, CD117, STAB2, CD56, and CD99 in tumor tissues after chemotherapy. Notably, RNA sequencing revealed a RNF213-SLC26A11 fusion in the tumor sample.ConclusionsThe BCOR-CCNB3 sarcoma with RNF213-SLC26A11 fusion may indicate a subset of tumors that undergo histopathological changes in response to chemotherapy. More similar cases in the future may help to clarify the clinical meanings of RNF213-SLC26A11 fusion in BCOR-CCNB3 sarcomas and the underlying mechanisms.

NTRK Fusions Detection in Paediatric Sarcomas to Expand the Morphological Spectrum and Clinical Relevance of Selected Entities.

Undifferentiated round cell sarcomas (URCS) of soft tissue and bone and tumours of uncertain differentiation (TUD) are commonly ascribed to a subset of neoplasms with low frequency of NTRK gene fusions. However, more recently NTRK-rearranged round and spindle cell tumours have been noted in case reports and in limited or heterogeneous cohorts. The aim of our study was to investigate the presence of NTRK gene fusions in a large retrospective cohort of paediatric URCS and TUD after a systematic review of the diagnosis, according to the recently updated WHO classification scheme. One-hundred and five patients with diagnosis of URCS or TUD, involving the bone or soft tissue, were retrospectively evaluated. After the case selection and the histopathological review of the case cohort, pan-Trk immunohistochemistry (IHC) testing was performed on formalin-fixed paraffin-embedded (FFPE) tissues. Tumour RNA was extracted from FFPE tissue and subjected to next-generation sequencing (NGS) library preparation, using a 10-gene NGS fusion panel, sequenced on an Illumina MiSeq. The NGS-positive cases were further confirmed by real-time PCR. On immunohistochemical screening, 12/105 (11.4%) cases were positive using the pan-Trk antibody, showing three different staining patterns with the cytoplasmic distribution being most common. Molecular analysis using NGS and confirmed by the real-rime PCR detected two positive cases for the ETV6-NTRK3 fusion. The histological pattern of the two positive cases, together with the demonstration of the NTRK rearrangement, leaded to re-classify these previously not otherwise specified sarcomas with uncertain differentiation into the emerging category of NTRK-rearranged neoplasms. In addition, we found the two NTRK fused neoplasms showing a clinical indolent course, in contrast with literature.

Intra- and extra-cranial BCOR-ITD tumours are separate entities within the BCOR-rearranged family.

BCOR‐ITD tumours form an emerging family of aggressive entities with an internal tandem duplication (ITD) in the last exon of the BCOR gene. The family includes cerebral tumours, termed central nervous system BCOR‐ITD (CNS BCOR‐ITD), and sarcomatous types described in the kidney as clear cell sarcoma of the kidney (CCSK), in the endometrium as high‐grade endometrial stromal sarcoma, and in the bone and soft tissue as undifferentiated round cell sarcoma or primitive myxoid mesenchymal tumour of infancy. Based on a series of 33 retrospective cases, including 10 CNS BCOR‐ITD and 23 BCOR‐ITD sarcomas, we interrogated the homogeneity of the entity regarding clinical, radiological, and histopathological findings, and molecular signatures. Whole‐transcriptomic sequencing and DNA methylation profiling were used for unsupervised clustering. BCOR‐ITD tumours mostly affected young children with a median age at diagnosis of 2.1 years (range 0–62.4). Median overall survival was 3.9 years and progression‐free survival was 1.4 years. This dismal prognosis is shared among tumours in all locations except CCSK. Histopathological review revealed marked differences between CNS BCOR‐ITD and BCOR‐ITD sarcomas. These two groups were consistently segregated by unsupervised clustering of expression (n = 22) and DNA methylation (n = 21) data. Proximity between the two groups may result from common somatic changes within key pathways directly related to the novel activity of the ITD itself. Conversely, comparison of gene signatures with single‐cell RNA‐Seq atlases suggests that the distinction between BCOR‐ITD sarcomas and CNS BCOR‐ITD may result from differences in cells of origin.

A small round blue cell tumour of the rib: A case report of Ewing sarcoma

Ewing sarcoma is a prototypical small round blue cell tumour with a characteristic EWSR1 translocation. We report a case of Ewing sarcoma arising in the rib of an 81-year-old female. The tumour was comprised of uniform small round cells which demonstrated an organoid growth pattern with a suggestion of rosette-like structures. Immunohistochemistry showed positive staining for CD99, vimentin and desmin; stains for cytokeratins, melanocytic markers, neuroendocrine markers, CD45, CD138, NFP and CD34 were negative. EMA and BCL2 demonstrated weak, patchy staining. FISH studies demonstrated an EWSR1 fusion, supporting the diagnosis of Ewing sarcoma. Desmin positivity, although recognised in Ewing sarcoma, has been reported in only 2% of cases.1 The main differential diagnosis based on morphology and immunohistochemistry was between Ewing sarcoma and synovial sarcoma due to CD99 positivity and focal EMA and BCL2 staining. However, EWSR1 translocations are not associated with synovial sarcoma.2 Recently a proportion of ‘undifferentiated round cell sarcomas’ with similar morphology to Ewing sarcoma have been divided into specific entities largely based on their molecular characteristics. These include CIC-rearranged sarcomas, sarcomas with BCOR alterations and round cell sarcomas with EWSR1-non ETS fusions.3

Distinct histologic and genetic characteristics of round cell sarcoma with CIC-DUX4 fusion and comparison with ewing sarcoma

CIC-DUX4 fusion gene associated sarcoma is a new emerging subgroup of round cell sarcoma with Ewing sarcoma-like morphology. Distinguishing these tumors from Ewing sarcoma family tumors (ESFT) is critical because of the clinical impact but is still challenging due to the overlapped histological and immunohistochemical phenotypes of each subtype. The present study investigated small round cell sarcoma to identify CIC-DUX4 fusion positive sarcoma, examined clinical, histopathologic and immunohistochemical characteristics of CIC-DUX4 sarcoma, and evaluated parameters to differentiate Ewing sarcoma family tumors. Seventy patients with undifferentiated round cell sarcoma or Ewing–like sarcoma were retrieved. Molecular tests including EWSR1, CIC break apart FISH, and RT-PCR for CIC-DUX4 gene fusion were performed and immunohistochemistry was performed. Six cases (8.6%) of CIC-DUX4 sarcomas were detected. Histologically, CIC-DUX4 sarcomas composed of heterogeneous round, plasmacytoid, and spindle cells and more commonly showed cytologic pleomorphism with bizarre nuclei and multinucleated cells and myxoid stoma unlike ESFT. CIC-DUX4 sarcomas didn’t show overall survival differences (p = 0.325) compared to ESFT but they demonstrated short disease-free survival (p = 0.034) and poor response to treatment (p = 0.007). Therefore, molecular analysis to detect the distinctive genetic alteration is mandatory in tumors with atypical histologic, immunohistochemical and/or clinical presentation for accurate diagnosis and treatment.

From the ashes of "Ewing-like" sarcoma: A contemporary update of the classification, immunohistochemistry, and molecular genetics of round cell sarcomas.

Round cell sarcomas include a diverse group of bone and soft tissue tumors, which comprise well-defined entities as well as several nascent categories presented in the 2020 World Health Organization classification. The morphologic overlap yet disparate nosology, prognostic implications, and management strategies places a high value on ancillary testing, including a strategic immunohistochemical approach and directed confirmation by cytogenetic and molecular genetic methods. We review the diagnostic categories that have emerged from the former wastebasket "undifferentiated round cell sarcoma" ("Ewing-like" sarcomas), with an emphasis on algorithmic exclusion of nonsarcomatous entities, diagnostic stratification of well-defined entities (Ewing sarcoma, rhabdomyosarcomas, poorly differentiated synovial sarcoma), and a discussion of the new categories with novel genetic alterations (CIC-rearranged sarcomas, sarcomas with BCOR genetic alterations, and round cell sarcomas with EWSR1-non-ETS fusions).

CIC-DUX4 sarcoma: A case report and review of the literature

CIC-DUX4 sarcoma is highly aggressive and rapidly develops lethal metastatic disease and chemoresistance. Its histology is similar to that of Ewing sarcoma and other small round cell sarcomas. Correlation with clinical data, radiological findings, pathological results (including immunohistochemistry and fluorescence in situ hybridization), and/or molecular techniques is necessary. We present the case of a 44-year-old woman who was initially diagnosed as having high-grade undifferentiated round cell sarcoma confirmed to be a CIC-DUX sarcoma by next-generation sequencing.

A Global CollaboRAtive Study of CIC-Rearranged, BCOR::CCNB3-Rearranged and Other Ultra-Rare Unclassified Undifferentiated Round Cell Sarcomas (GRACefUl)

A Global CollaboRAtive Study of CIC-Rearranged, BCOR::CCNB3-Rearranged and Other Ultra-Rare Unclassified Undifferentiated Round Cell Sarcomas (GRACefUl)

Undifferentiated and dedifferentiated soft tissue neoplasms: Immunohistochemical surrogates for differential diagnosis.

Undifferentiated soft tissue sarcomas (USTS) are described in the current World Health Organization Classification of Soft Tissue and Bone Tumours as those showing no identifiable line of differentiation when analyzed by presently available technologies. This is a markedly heterogeneous group, and the diagnosis of USTS remains one of exclusion. USTS can be divided into four morphologic subgroups: pleomorphic, spindle cell, round cell and epithelioid undifferentiated sarcomas, with this combined group accounting for up to 20% of all soft tissue sarcomas. As molecular advances enable the stratification of emerging genetic subsets within USTS, particularly within undifferentiated round cell sarcomas, other groups, particularly the category of undifferentiated pleomorphic sarcomas (UPS), still remain difficult to substratify and represent heterogeneous collections of neoplasms often representing the common morphologic endpoints of a variety of malignant tumors of various (mesenchymal and non-mesenchymal) lineages. However, recent molecular developments have also enabled the identification and correct classification of many tumors from various lines of differentiation that would previously have been bracketed under 'UPS'. This includes pleomorphic neoplasms and dedifferentiated neoplasms (the latter typically manifesting with an undifferentiated pleomorphic morphology) of mesenchymal (e.g. solitary fibrous tumor and gastrointestinal stromal tumor) and non-mesenchymal (e.g. melanoma and carcinoma) origin. The precise categorization of 'pleomorphic' or 'undifferentiated' neoplasms is critical for prognostication, as, for example, dedifferentiated liposarcoma typically behaves less aggressively than other pleomorphic sarcomas, and for management, including the potential for targeted therapies based on underlying recurrent molecular features. In this review we focus on undifferentiated and dedifferentiated pleomorphic and spindle cell neoplasms, summarizing their key genetic, morphologic and immunophenotypic features in the routine diagnostic setting, and the use of immunohistochemistry in their principal differential diagnosis, and highlight new developments and entities in the group of undifferentiated and dedifferentiated soft tissue sarcomas.