Undifferentiated Small Round Cell Sarcoma Research Articles

Proteomic Characterization of Undifferentiated Small Round Cell Sarcomas With EWSR1 and CIC::DUX4 Translocations Reveals Diverging Tumor Biology and Distinct Diagnostic Markers

Undifferentiated small round cell sarcomas (USRS) of bone and soft tissue are a group of tumors with heterogenic genomic alterations sharing similar morphology. In the present study, we performed a comparative large-scale proteomic analysis of USRS (n = 42) with diverse genomic translocations including classic Ewing sarcomas with EWSR1::FLI1 fusions (n = 24) or EWSR1::ERG fusions (n = 4), sarcomas with an EWSR1 rearrangement (n = 2), CIC::DUX4 fusion (n = 8), as well as tumors classified as USRS with no genetic data available (n = 4). Proteins extracted from formalin-fixed, paraffin-embedded pretherapeutic biopsies were analyzed qualitatively and quantitatively using shotgun mass spectrometry (MS). More than 8000 protein groups could be quantified using data-independent acquisition. Unsupervised hierarchical cluster analysis based on proteomic data allowed stratification of the 42 cases into distinct groups reflecting the different molecular genotypes. Protein signatures that significantly correlated with the respective genomic translocations were identified and used to generate a heatmap of all 42 sarcomas with assignment of cases with unknown molecular genetic data to either the EWSR1- or CIC-rearranged groups. MS-based prediction of sarcoma subtypes was molecularly confirmed in 2 cases where next-generation sequencing was technically feasible. MS also detected proteins routinely used in the immunohistochemical approach for the differential diagnosis of USRS. BCL11B was highly expressed in Ewing sarcomas, and Bach2 as well as ETS-1 were highly expressed in CIC::DUX4-associated sarcomas, were among proteins identified by the present proteomic study, and were chosen for immunohistochemical confirmation of MS data in our study cohort. Differential expressions of these 3 markers in the 2 genetic groups were further validated in an independent cohort of n = 34 USRS. Finally, our proteomic results point toward diverging signaling pathways in the different USRS subgroups.

Differential cyclin-E1 expression in CIC-rearranged sarcoma

CIC-rearranged sarcoma (CRS) is a group of high-grade undifferentiated small round cell sarcomas examined as a separate entity in the current WHO classification; since it shows more aggressive clinical behavior and distinct morphological and molecular features compared to Ewing sarcoma (ES). As CCNE1 expression is associated with tumor growth in CIC::DUX4 sarcomas, we aimed to demonstrate the value of cyclin E1 expression in CRS. Cyclin E1 immunohistochemistry and break-apart FISH for EWSR1 and CIC gene rearrangements were performed on 3-mm tissue microarrays composed of 40 small round cell tumors. Five cases were classified as CRS, whereas 22 were ES and 13 were unclassified (EWSR1-/CIC-). Among all three diagnostic groups, we found cyclin E1 expression level to be higher in CRS (80 %) and unclassified groups (61.5 %) compared to ES (4.5 %, p < 0.001). In addition, high cyclin E1 expression levels were associated with higher mean age at diagnosis, presence of atypical histology and myxoid stroma, low CD99 expression, and presence of metastasis at diagnosis. The sensitivity and specificity of high cyclin E1 expression in detecting non-ES cases were 95.5 % and 66.7 %, respectively. However, the correlation between cyclin E1 expression level and survival was not statistically significant. This is the first study that shows cyclin E1 immunohistochemical expression in EWSR1-negative undifferentiated small cell sarcomas, particularly CRS.

Clinical outcomes of patients with CIC-rearranged sarcoma: a single institution retrospective analysis

PurposeCIC-rearranged sarcomas represent a type of undifferentiated small round cell sarcoma (USRCS) characterized by poor survival, rapid development of chemotherapy resistance, and high rates of metastasis. We aim to contribute to the growing body of knowledge regarding diagnosis, treatment, clinical course, and outcomes for these patients.MethodsThis case series investigates the clinical courses of ten patients with CIC-rearranged sarcoma treated at the Johns Hopkins Hospital from July 2014 through January 2024. Clinical data were retrospectively extracted from electronic medical records.ResultsPatients ranged from 10 to 67 years of age at diagnosis, with seven patients presenting with localized disease and three with metastatic disease. Tumors originated from soft tissues of various anatomic locations. Mean overall survival (OS) was 22.1 months (10.6–52.2), and mean progression-free survival (PFS) was 16.7 months (5.3–52.2). Seven patients received intensive systemic therapy with an Ewing sarcoma-directed regimen or a soft tissue sarcoma-directed regimen. Three patients experienced prolonged disease-free survival without systemic treatment.ConclusionMost patients in this case series demonstrated aggressive clinical courses consistent with those previously described in the literature, although we note a spectrum of clinical outcomes not previously reported. The diversity of clinical courses underscores the need for an improved understanding of individual tumor biology to enhance clinical decision-making and patient prognosis. Despite its limitations, this article broadens the spectrum of reported clinical outcomes, providing a valuable addition to the published literature on this rare cancer.

Spontaneous expression of the CIC::DUX4 fusion oncoprotein from a conditional allele potently drives sarcoma formation in genetically engineered mice.

CIC::DUX4 sarcoma (CDS) is a rare but highly aggressive undifferentiated small round cell sarcoma driven by a fusion between the tumor suppressor Capicua (CIC) and DUX4. Currently, there are no effective treatments and efforts to identify and translate better therapies are limited by the scarcity of patient tumor samples and cell lines. To address this limitation, we generated three genetically engineered mouse models of CDS (Ch7CDS, Ai9CDS, and TOPCDS). Remarkably, chimeric mice from all three conditional models developed spontaneous soft tissue tumors and disseminated disease in the absence of Cre-recombinase. The penetrance of spontaneous (Cre-independent) tumor formation was complete irrespective of bi-allelic Cic function and the distance between adjacent loxP sites. Characterization of soft tissue and presumed metastatic tumors showed that they consistently expressed the CIC::DUX4 fusion protein and many downstream markers of the disease credentialing the models as CDS. In addition, tumor-derived cell lines were generated and ChIP-seq was preformed to map fusion-gene specific binding using an N-terminal HA epitope tag. These datasets, along with paired H3K27ac ChIP-sequencing maps, validate CIC::DUX4 as a neomorphic transcriptional activator. Moreover, they are consistent with a model where ETS family transcription factors are cooperative and redundant drivers of the core regulatory circuitry in CDS.

Expression of NKX2.2 in undifferentiated small round cell sarcoma and its diagnostic value

Expression of NKX2.2 in undifferentiated small round cell sarcoma and its diagnostic value

Clinicopathological Features of Primary Renal Mesenchymal Neoplasms in Adults: A Cross-sectional Study

Introduction: Renal mesenchymal tumours are a subset of primary renal tumours arising from the mesenchymal tissue in the kidney. They are a heterogeneous group of mostly benign tumours that exhibit varied behaviours and molecular characteristics. Aim: To analyse the wide spectrum of histological subtypes, their unique clinical presentation, and pathological features of primary renal mesenchymal neoplasms. Materials and Methods: This was a retrospective crosssectional observational clinicopathological study conducted in Department of General Pathology, Christian Medical College, tertiary care hospital, Vellore, Tamil Nadu, India, looking at data of adult Primary Renal Mesenchymal Tumours (PRMT) for a 15- year period between January 2006 and March 2021. Clinical details such as age, presenting symptoms, and tumour size were obtained from the hospital information system. Histopathology and immunohistochemical slides were reviewed for all the cases. Additional Immunohistochemistry (IHC) and molecular studies were performed for the undifferentiated sarcomas. The tumours were categorised into three groups as recommended by the World Health Organisation (WHO) 2020 classification of soft-tissue tumours based on biological behaviour: benign, intermediate, and malignant. Continuous variables are expressed as mean and Standard Deviation (SD). Comparison of categorical variables between groups was performed using the Chi-squared test. Continuous variables between groups were compared using the Student’s t-test for significance. A p-value of less than 0.05 was considered statistically significant. Results: Of the 2164 nephrectomies performed for neoplastic conditions, 97 (4.5%) were diagnosed as renal mesenchymal tumours. There were 59 (60.8%) benign, 10 (10.3%) with intermediate biologic behaviour and 28 (28.9%) malignant tumours. The mean ages at presentation were 40.5 years for benign, 43.4 years for intermediate, and 41 years for malignant tumours, respectively. Haematuria was seen in 11 of 38 (29%) intermediate grade and malignant tumours and in only 6 of 59 (10%) benign tumours, a difference that was statistically significant (p-value=0.017). Malignant tumours 24 of 28 (86%) were more likely to be larger (&gt;7 cm) when compared to benign tumours 28 of 59 (47%) at the time of presentation (p-value=0.027). Classical angiomyolipomas constituted 53/59 (90%) of the benign tumours. Of the 10 intermediate grade tumours, epithelioid angiomyolipomas and solitary fibrous tumours were the most common, accounting for 50% and 30% of the intermediate group, respectively. Undifferentiated small round cell sarcoma was the most common malignant neoplasm, making up 12/28 (43%) of the malignant tumours. Conclusion: The present study found that renal mesenchymal tumours constitute a small but unique group of renal tumours. They are predominantly benign, but up to a quarter are malignant. Malignant tumours tend to be larger and more often present with haematuria. The present study highlights the importance of IHC in the diagnosis of intermediate and malignant mesenchymal tumours and the requirement of exhaustive molecular studies individually tailored to the immuno-profile of malignant tumours.

Undifferentiated Small Round Cell Sarcoma of the Hypopharynx in a 7-Month-Old Patient.

Undifferentiated small round cell sarcoma is an extremely rare and highly aggressive tumor touching the soft tissues and bones. Here, we report the case of a 7-month-old girl who presented to our department with respiratory distress due to a hypopharyngeal mass causing airway obstruction. The patient underwent a tracheotomy and had a direct laryngoscopy. Histological examination confirmed the diagnosis of an undifferentiated small round cell sarcoma. The patient received chemotherapy and radiotherapy and underwent neck dissection. One year later, the patient was diagnosed with local recurrence as well as metastatic cervical nodes and liver and pulmonary metastases. The case is original by the tumor's location and the age of onset. To the best of our knowledge, this could be the first case in English and French literature reporting an undifferentiated small round cell sarcoma affecting the hypopharynx among infants. The purpose of this article is to report our case and discuss its clinical and anatomopathological features as well as its prognosis and treatment options.

Genetically Engineered Mouse Models of CIC-DUX4 Sarcoma Reveal an Unexpected Sensitivity to Histone Deacetylase (HDAC) Inhibition

Undifferentiated small round cell sarcomas constitute a highly aggressive subtype of soft tissue sarcoma that affects adolescents and young adults. Frequently, these cancers are caused by a gene fusion between the DNA binding domain of capicua (CIC), a canonical tumor suppressor that normally acts as a transcriptional repressor, with the transcriptional activation domain of double homeobox 4 (DUX4). Given the rare nature of CIC-DUX4 sarcoma (CDS), obtaining patient tissues to study the mechanisms of disease is very challenging. Moreover, conducting clinical trials to identify radiosensitizers or other novel treatments is not possible underscoring the need for a primary animal model. Here, we report the development and characterization of the first genetically engineered mouse model of CDS and the use of this model to investigate novel therapies. Using Cre-loxP technology, three genetically engineered mouse models of CDS were developed. The resulting tumors were characterized by hematoxylin and eosin (H&E) staining, immunohistochemistry (IHC), and RNA-sequencing. Cell lines from multiple primary and metastatic tumors were derived and used for Chromatin Immunoprecipitation (ChiP) sequencing, Rapid Immunoprecipitation mass spectrometry of Endogenous proteins (RIME), and targeted drug screening. In all three models, spontaneous (Cre-independent) recombination occurred in chimeric animals resulting in the formation of soft tissue tumors, widespread metastasis to the lungs, liver, and brain, and 100% lethality within 4-8 weeks of life. The tumors histologically resembled human CDS and stained positive for an HA (hemagglutinin) epitope tag confirming transgene expression. Of 108 chimeric pups (generation 0, G0), only one male bred before succumbing to metastatic disease. G2 progeny now exhibit resistance to spontaneous recombination and tumor development enabling reliable propagation of one of the models for experimentation. Using tumor derived cell lines for integrative analyses of multi-omics datasets, we find evidence for a model where CIC-DUX4 functions as a neomorphic and oncogenic transcriptional activator, which cooperates with ETS family transcription factors to drive the CDS transcriptional program. Lastly, small molecule epigenetic drug screens in mouse and human CDS cell lines point to an unexpected sensitivity to HDAC inhibitors, which we hypothesize may be attributable to ETS factor hyperactivity. Genetically engineered mouse models of CIC-DUX4 sarcoma form tumors that recapitulate the human disease. Using mouse tumors and tumor-derived cell lines, we identify a mechanistic role and potential therapeutic vulnerability that converges on the ETS family transcription factors.

458 Primary Renal Mesenchymal Neoplasms: A Retrospective Clinicopathological Study

Abstract Aim Mesenchymal tumors are rare primary neoplasms of the kidney with limited demographic data in literature. We sought to study the prevalence of this rare subset of tumors in adults, at our tertiary care hospital focusing on the pathological and radiological characteristics. Method Clinico-radiological and intra-operative details were retrospectively analyzed for adult primary renal mesenchymal neoplasms received between 2006 and 2021 and correlated with the histopathology data. Results Of 2164 nephrectomies performed for neoplastic conditions, 97 (4.5%) were diagnosed as renal mesenchymal tumors. There were 59 (60.8%) benign, 10 (10.3%) with intermediate biologic behavior and 28 (28.9%) malignant tumors. The mean age was similar across these categories. Hematuria was seen in 11 of 38 (29%) intermediate grade and malignant tumors and in only 6 of 59 (10%) benign tumors a difference that was statistically significant (p = 0.017). Tumors ≥ 7cm were more likely to be malignant/intermediate grade than benign (p = 0.027). Classical angiomyolipomas constituted 90% of the benign tumors. Epithelioid angiomyolipomas and solitary fibrous tumors were the common intermediate grade tumors. Undifferentiated small round cell sarcoma was the most common malignant neoplasm. Immunohistochemical and molecular studies were useful for confirmation of diagnosis, particularly in cases of intermediate/malignant tumors. Conclusions Mesenchymal tumors constitute 4.5% of adult primary renal tumors, are predominantly benign tumors but are malignant in 1/4 th of cases. Malignant tumors are typically larger and more often present with hematuria. Immunohistochemistry (IHC) and molecular studies play a role in the diagnosis of intermediate and malignant mesenchymal tumors.

Impact of age on survival according to molecular tumor findings in children and adolescents with soft-tissue and bone sarcoma: The BIOSCA project

BackgroundAdolescents (15–19 years) with sarcoma are known to have significantly worse survival than children (0–14 years). One possible reason may be that the adolescent sarcomas exhibit specific biological characteristics resulting in differences in clinical presentation and treatment resistance behaviors. The BIOSCA project aims to further explore these age-related differences in survival accounting for molecular tumor characteristic in children and adolescents with sarcoma. MethodsA retrospective national population-based observational study with documented somatic genetic analyses was conducted between 2011 and 2016 of all patients aged from 0 to 17 years with a diagnosis of sarcoma using the National Registry of Childhood Cancers Database. ResultsA total of 1637 children (0–9years: 40%), preadolescents (10–14years: 35%) and adolescents (15–17 years: 25%) with a diagnosis of bone (N = 845) or soft-tissue (N = 792) sarcoma were included. Adolescents had significantly worse outcome for undifferentiated small round cell sarcoma (USRCS), alveolar rhabdomyosarcoma (ARMS), and epithelioid sarcoma. Five-year overall survivals were worse among CIC-rearranged USRCS cases (47% [95%CI:21–69]) as compared to other USRCS, and PAX3::FOXO1 ARMS patients (44% [95%CI:32–55]) as compared to other ARMS. Adjusting for stage and genomic-profiling status, adolescents with USRCS were 1.6-fold more likely to die than children (P = 0.05), while the difference in survival between age of ARMS patients was weaken. Indeed, the prevalence of PAX3::FOXO1 increased significantly with age. ConclusionAge was an independent prognostic factor of outcome only in patients with USRCS, while the association between age and survival of patients with ARMS could be partly explained by differences in prevalence of PAX3::FOXO1.

Identification of novel actionable SNVs using targeted comprehensive genome profiling in patients with sarcoma.

e23520 Background: The utility of comprehensive genome profiling is not well validated in early-stage sarcoma. The 5-year survival rate for metastatic sarcoma is less than 20%. The application of comprehensive Next Generation Sequencing (NGS) on tumor DNA has led to the identification of a multitude of actionable alterations in oncogenes &amp; tumor suppressor genes alongside the detection of immunotherapy markers like microsatellite instability, tumor mutational burden, and homologous recombinant deficiency. Methods: We retrospectively analyzed ccfDNA and gDNA in 13 sarcoma patients by targeted Next Generation Sequencing (NGS) using OncoIndx proprietary gene panel that targets exonic regions of 600 cancer-related genes. Illumina-compatible libraries were prepared by the target hybridization method and sequenced on Nextseq 2000 platform in a pair-end fashion. Variant calling was performed using an indigenously developed bioinformatics pipeline. Results: Here we report for the first time the identification of several, novel mutations in rare sarcomas such as IDH2R140W (in epithelioid hemangioendothelioma), CTNNB1D32V (in undifferentiated small round cell sarcoma) and DDR2M754I (in osteosarcoma). Furthermore, we observed, JAK1 amplification and BRAF-GUSBP1 fusion in osteosarcoma and a sarcomatoid carcinoma case, respectively. JAK1 amplification and DDR2M754I were found in the same patient. The IDH2 mutation and JAK1 amplification could find potential applications for JAK1 and IDH2 inhibitors respectively. Similarly, cancers having DDR2 mutations are known to respond to multikinase inhibitors such as Imatinib and Dasatinib, thus making a strong case for the potential repurposing of these drugs in sarcomas. ~93% of patients demonstrated genome-wide instabilities as evidenced by LOH, LST, TAI, and high TMB. Homologous Recombinant deficiency was found in 66.7% of patients. Although this is a small patient population, the high HRD+ percentages point to the underappreciated importance of HRD testing in sarcoma and herald the use of PARPi therapy for sarcoma. Conclusions: We identified several actionable mutations in rare sarcoma cases. These findings highlight the power of comprehensive genome profiling like the OncoIndx panel and warrant further studies on the role of IDH2, JAK1, and BRAF fusion in sarcomas. Moreover, they also present a strong potential case for repurposing of TKI such as Imatinib and Dasatinib in sarcomas.

The clinical value of tumor-informed minimal residual disease detection in sarcoma.

11510 Background: The high recurrence and metastasis rates lead to poor survival of patients with sarcoma. At present, circulating tumor DNA-based minimal residual disease (MRD) has been studied in varies solid tumors and proved to be valuable in guiding treatment and predicting recurrence, but its application in sarcomas is rarely reported. Methods: Tumor tissue samples were used for whole exome sequencing (WES) and clonal mutations were selected for the customized MRD panel. Blood samples were collected for MRD detection. Experiments were conducted at OrigiMed, a College of American Pathologists accredited and Clinical Laboratory Improvement Amendments certified laboratory. Results: A total of 84 sarcoma patients including 47 bone tumor (BT), 32 soft-tissue sarcoma (STS), and 5 undifferentiated small round cell sarcoma (USRCS) patients were enrolled. Patients consisted of 49 (58.3%) males and 35 (41.7%) females, with a median age of 23 years old (1-85 years old). Based on WES, we found that 64% (4936/7715) of the mutated genes were unique to each patient, and 70.4% (859/1220) of selected tumor-informed single nucleotide variants (SNV) were variants with unknown significance, suggesting that tumor-informed MRD is superior to panel-based MRD in sarcomas. In this cohort, 78.6% (66/84) of patients successfully constructed MRD panels, including 85.1% (40/47) of BT patients, 75% (24/32) of STS patients, and 40% (2/5) of USRCS patients. The main reason for failure was the scarcity of SNVs detected. Preoperative MRD detection was performed on 6 cases and revealed a positive rate of 100%. MRD detection was performed twice on 2 patients during preoperative neoadjuvant therapy. For the patient with constant allele frequencies detected throughout the treatment course, imaging showed tumor enlargement; While for another patient with a trend of reduction in allelic frequency, imaging showed tumor shrinkage and necrotic tumor tissue was observed in surgery one month later. These two patients had not recurred after surgery at the time of analysis. Post-surgery MRD detection were performed on 27 patients, of which 1 STS and 7 BTs were positive (30%, 8/27). Three of them confirmed recurrence by imaging at 12, 30, and 101 days after detection of positive MRD, respectively. However, there were still no imaging recurrence in the other patients so far, including the 5 remaining patients with positive MRD and 19 patients with negative MRD. Follow-up is still ongoing. Conclusions: MRD tests had been successfully performed in most of the sarcoma patients. Due to the heterogeneity of sarcomas, about 64% of mutated genes of sarcomas are unique individually, which may be more suitable for monitoring with tumor-informed MRD panel. Tumor-informed MRD could be used to predict the efficacy of preoperative neoadjuvant therapy and discover recurrence earlier than imaging in sarcoma.

Ewing sarcoma

Ewing sarcoma, according to the latest 2020 WHO classification of tumors of bone and soft tissue, belongs to the category of “undifferentiated small round cell sarcomas of bone and soft tissue.” After osteosarcoma, it is the second most common malignant bone tumor in children and young adults. Most Ewing sarcomas develop in the bone and about 30% of soft tissues. In this paper, all the epidemiological, clinical and imaging characteristics will be reviewed.

Update of pediatric bone tumors-other mesenchymal tumors of bone, hematopoietic neoplasms of bone, and WHO classification of undifferentiated small round cell sarcomas of bone.

There are numerous bone tumors in the pediatric population, with imaging playing an essential role in diagnosis and management. Our understanding of certain bone tumors has rapidly evolved over the past decade with advancements in next-generation genetic sequencing techniques. This increased level of understanding has altered the nomenclature, management approach, and prognosis of certain lesions. We provide a detailed update of bone tumors that occur in the pediatric population with emphasis on the recently released nomenclature provided in the 5th edition of the World Health Organization Classification of Soft Tissue and Bone Tumours. We discuss other mesenchymal tumors of bone, hematopoietic neoplasms of bone, and WHO classification of undifferentiated small round cell sarcomas of bone. We have detailed osteogenic tumors and osteoclastic giant cell-rich tumors, as well as notochordal tumors, chondrogenic tumors, and vascular tumors of the bone in separate manuscripts.

A global collaboRAtive study of CIC-rearranged, BCOR::CCNB3-rearranged and other ultra-rare unclassified undifferentiated small round cell sarcomas (GRACefUl)

BackgroundUndifferentiated small round cell sarcomas (URCSs) represent a diagnostic challenge, and their optimal treatment is unknown. We aimed to define the clinical characteristics, treatment, and outcome of URCS patients. MethodsURCS patients treated from 1983 to 2019 at 21 worldwide sarcoma reference centres were retrospectively identified. Based on molecular assessment, cases were classified as follows: (1) CIC-rearranged round cell sarcomas, (2) BCOR::CCNB3-rearranged round cell sarcomas, (3) unclassified URCSs. Treatment, prognostic factors and outcome were reviewed. ResultsIn total, 148 patients were identified [88/148 (60%) CIC-rearranged sarcoma (median age 32 years, range 7–78), 33/148 (22%) BCOR::CCNB3-rearranged (median age 17 years, range 5–91), and 27/148 (18%) unclassified URCSs (median age 37 years, range 4–70)]. One hundred-one (68.2%) cases presented with localised disease; 47 (31.8%) had metastases at diagnosis. Male prevalence, younger age, bone primary site, and a low rate of synchronous metastases were observed in BCOR::CCNB3-rearranged cases. Local treatment was surgery in 67/148 (45%) patients, and surgery + radiotherapy in 52/148 (35%). Chemotherapy was given to 122/148 (82%) patients. At a 42.7-month median follow-up, the 3-year overall survival (OS) was 92.2% (95% CI 71.5–98.0) in BCOR::CCNB3 patients, 39.6% (95% CI 27.7–51.3) in CIC-rearranged sarcomas, and 78.7% in unclassified URCSs (95% CI 56.1–90.6; p < 0.0001). ConclusionsThis study is the largest conducted in URCS and confirms major differences in outcomes between URCS subtypes. A full molecular assessment should be undertaken when a diagnosis of URCS is suspected. Prospective studies are needed to better define the optimal treatment strategy in each URCS subtype.

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.

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.

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.