Small Round Cell Tumor Research Articles

Review of Imaging Peritoneal Disease and Treatment.

Peritoneal disease can be classified as either benign or malignant in nature. Malignant peritoneal disease can be further considered as either primary or secondary in origin. Primary peritoneal malignancy includes peritoneal mesothelioma, serous carcinoma, and desmoplastic small round cell tumour. Peritoneal carcinomatosis is the most commonly encountered secondary malignant peritoneal disease, typically of ovarian, gastric, colorectal, pancreatic, small bowel neuroendocrine, or breast origin. Others include peritoneal lymphomatosis and sarcomatosis. Benign peritoneal pathology may mimic malignant disease. Differentiating benign from malignant peritoneal pathology can be challenging, but is critical to guide appropriate care and avoid unnecessary intervention. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) offers potentially curative treatment for patients with peritoneal carcinomatosis, pseudomyxoma peritonei, and peritoneal mesothelioma. For such patients, the radiologist provides crucial pre-operative information highlighting sites of disease involvement, particularly for sites which are challenging to assess at laparotomy or laparoscopy, including the hepatic dome, subdiaphragmatic space and mesenteric root. The radiologist is also essential to identify potential contraindications to surgery, as well as interpreting normal post-operative appearances, complications and assessing for disease recurrence.

Pelvic Desmoplastic Small Round Cell Tumor on 18F-PSMA PET/CT

Abstract Desmoplastic small round cell tumor (DSRCT) as a subtype of sarcoma is rare and aggressive. We present the case of a 23-year-old man with a histologically confirmed DSRCT who underwent 18F-PSMA PET/CT before prostate biopsy and surgical resection of the tumor. It is well known that PSMA PET has a high accuracy for detecting clinically significant prostate adenocarcinoma and is useful in guiding prostate biopsy. This case signifies DSRCT can also exhibit intermediate PSMA expression on 18F-PSMA PET/CT.

Emerging round cell sarcomas in children.

Several distinctive round cell sarcomas have emerged by leveraging new testing modalities to include immunohistochemistry, next-generation sequencing, methylation array, and others. While Ewing sarcoma has led the way as the prototypic round cell sarcoma, more recently described round cell sarcomas of bone and soft tissue are now recognized which have unique clinical, morphologic, immunophenotypic, and genetic signatures. While each of these entities is less common than Ewing sarcoma, it is important to distinguish these tumors for correct diagnosis, prognostication, and potential treatment management. The focus of this review will cover CIC-rearranged sarcoma, BCOR-altered sarcomas, and EWSR1-non-ETS sarcomas to include recent developments in desmoplastic small round cell tumor as well as sarcomas with EWSR1/FUS::NFATc2 and EWSR1::PATZ1 gene fusions, highlighting the clinical, morphologic, and immunophenotypic clues to the diagnosis with recognition of each molecular diagnostic hallmark.

BCOR-ITD Rearranged Sarcoma in the Mandible of a 5-Year-Old Child: A Case Report Highlighting Diagnostic Distinction From Odontogenic Fibromyxoma.

The 5th edition of the World Health Organization (WHO) classification of soft tissue and bone has recognized three distinct groups among Ewing-like sarcomas, namely, CIC-rearranged sarcoma, sarcomas with BCOR genetic alterations, and round cell sarcomas with EWSR1:: non-ETS fusions. Sarcomas with BCOR genetic alterations are a distinct clinicopathological group of high-grade tumors, representing 5% of small round cell tumors. BCOR-ITD rearranged tumors commonly manifest as spindle cell sarcomas and many of them display low cellularity with monomorphous cell morphology and myxoid background resembling benign fibroblastic tumors. We present an intriguing case report of a 5-year-old boy diagnosed with a moderately cellular mandibular spindle cell tumor exhibiting BCOR-ITD rearrangement which was initially misdiagnosed as an odontogenic fibromyxoma. This case report illustrates the histological and immunophenotypic findings of BCOR-ITD rearranged sarcoma, requiring a comprehensive immunohistochemical panel and additional molecular tests for accurate diagnosis.

Adult supratentorial peripheral primitive neuroectodermal tumor with multiple metastases: a case report and literature review

BackgroundIntracranial primitive neuroectodermal tumors (PNETs) are characterized by poorly differentiated, highly malignant, aggressive small round tumor cells originating from the central and peripheral nervous systems.Case presentationA 25-year-old Chinese woman experienced sudden onset headache, vomiting, and severe anemia. Imaging examinations revealed a mass in the left parietal occipital lobe. Following microsurgery, histological confirmation revealed the tumor to be pPNET. Postoperative computed tomography (CT) showed multiple metastases in the lung, liver, and retroperitoneal lymph node. Unfortunately, she died of tumor cachexia 1 month after chemotherapy.ConclusionsDue to the rare presentation of pPNET, pPNET would be misdiagnosed without the histological diagnosis. Here, we aimed to provide clinicians with information about the treatment and relevant literature of pPNET.

Replication Stress is an Actionable Genetic Vulnerability in Desmoplastic Small Round Cell Tumors.

Desmoplastic small round cell tumor (DSRCT) is an aggressive sarcoma subtype that is driven by the EWS-WT1 chimeric transcription factor. The prognosis for DSRCT is poor, and major advances in treating DSCRT have not occurred for over two decades. To identify effective therapeutic approaches to target DSRCT, we conducted a high-throughput drug sensitivity screen in a DSRCT cell line assessing chemosensitivity profiles for 79 small-molecule inhibitors. DSRCT cells were sensitive to PARP and ATR inhibitors (PARPi, ATRi), as monotherapies and in combination. These effects were recapitulated using multiple clinical PARPi and ATRi in three biologically distinct, clinically-relevant models of DSRCT, including cell lines, a patient-derived xenograft (PDX)-derived organoid model, and a cell line-derived xenograft mouse model. Mechanistically, exposure to a combination of PARPi and ATRi caused increased DNA damage, G2/M checkpoint activation, micronuclei accumulation, replication stress, and R-loop formation. EWS-WT1 silencing abrogated these phenotypes and was epistatic with exogenous expression of the R-loop resolution enzyme RNase H1 in reversing the sensitivity to PARPi and ATRi monotherapies. The combination of PARPi and ATRi also induced EWS-WT1-dependent cell-autonomous activation of the cGAS/STING innate immune pathway and cell surface expression of PD-L1. Taken together, these findings point towards a role for EWS-WT1 in generating R-loop-dependent replication stress that leads to a targetable vulnerability, providing a rationale for the clinical assessment of PARPi and ATRi in DSRCT.

Desmoplastic Small Round Cell Tumor of the Spinal Canal: A Rare Presentation in a Female Pediatric Patient

AbstractDesmoplastic small round cell tumor (DSRCT) is a rare and aggressive malignancy primarily affecting young individuals, typically originating in the abdominal cavity. While spinal involvement by DSRCT is exceedingly rare, especially in pediatric patients, recognizing such atypical presentations is crucial for optimal management. Here, we present a case of DSRCT involving the spinal canal in a 3-year-old female child, representing one of the youngest documented instances in the literature. Initial symptoms included weakness, lower limb pain, and urinary incontinence. Magnetic resonance imaging revealed an enhancing soft tissue lesion in the spinal canal, prompting tumor excision and histopathological examination. The tumor exhibited characteristic features of DSRCT, including small round cells within a desmoplastic stroma. Immunohistochemistry confirmed the diagnosis, showing positivity for Wilms tumor 1, epithelial membrane antigen, desmin, and synaptophysin. This case highlights the challenges in diagnosing and managing rare tumors like spinal DSRCT, emphasizing the importance of a comprehensive approach to differential diagnosis and individualized treatment strategies.

Nuclear DUX4 immunohistochemistry is a highly sensitive and specific marker for the presence of CIC::DUX4 fusion in CIC-rearranged sarcomas: a study of 48 molecularly confirmed cases.

CIC-rearranged sarcomas (CRS) are clinically aggressive undifferentiated round cell sarcomas (URCS), commonly driven by CIC::DUX4. Due to the repetitive nature of DUX4 and the variability of the fusion breakpoints, CIC::DUX4 fusion may be missed by molecular testing. Immunohistochemical (IHC) stains have been studied as surrogates for the CIC::DUX4 fusion. We aim to assess the performance of DUX4 IHC in the work-up of CRS and its expression in non-CRS round cell or epithelioid neoplasms. Cases of molecularly confirmed CRS (n = 48) and non-CRS (n = 105) were included. CRS cases consisted of 35 females and 13 males, with ages ranging from less than 1 year to 67 years (median = 41 years). Among the molecularly confirmed non-CRS cases, C-terminal DUX4 expression was investigated in Ewing sarcomas (38 cases), alveolar rhabdomyosarcomas (18 cases), desmoplastic smallround cell tumours (12 cases) and synovial sarcomas (n = five), as well as in non-mesenchymal neoplasms such as SMARCA4/SMARCB1-deficient tumours (n = five), carcinomas of unknown primary (n = three) and haematolymphoid neoplasms (four cases). DUX4 IHC was considered positive when strong nuclear expression was detected in more than 50% of neoplastic cells. When used as a surrogate for the diagnosis of CRS, the sensitivity and specificity of DUX4 IHC was 98 and 100%, respectively. Only one CRS case was negative for DUX4 IHC and harboured a CIC::FOXO4 fusion. DUX4 IHC is a highly sensitive and specific surrogate marker for the presence of CIC::DUX4 fusion, demonstrating its utility in establishing a diagnosis of CRS.

Myeloid sarcomas with CBFA2T3 : GLIS2 fusion: clinicopathologic characterization of 4 cases mimicking small round cell tumors.

Acute myeloid leukemia with CBFA2T3::GLIS2 fusion can initially present as extramedullary lesions (myeloid sarcoma), leading to a misdiagnosis of nonhematologic pediatric solid tumors. We characterized the clinicopathologic features of 4 cases of CBFA2T3::GLIS2 fusion-positive myeloid sarcoma in pediatric patients where the sarcoma presented either without leukemic involvement (isolated myeloid sarcoma; 3/4 [75%]) or had concurrent leukemic disease (1/4 [25%]). All cases mimicked nonhematopoietic tumors at morphologic and immunophenotypic levels, so the initial evaluation did not raise suspicion for acute myeloid leukemia/myeloid sarcoma. After extensive workup, however, including molecular studies, the diagnosis of myeloid sarcoma with CBFA2T3::GLIS2 fusion was rendered. This study highlights the need for a high suspicion index of GLIS2-rearranged myeloid sarcoma in the differential diagnosis of pediatric small round cell tumors in tissue biopsies and the application of adequate workup to avoid misdiagnosing this entity.

Pediatric soft tissue tumors : Tumors of uncertain origin

Soft tissue tumors of childhood are an extremely heterogeneous group of tumors that require precise diagnosis for therapy. In this article, selected tumors of uncertain origin that exhibit characteristic histological, immunophenotypical, and molecular features are addressed. Angiomatoid fibrous histiocytoma, alveolar soft part sarcoma, extrarenal rhabdoid tumor, synovial sarcoma, and desmoplastic small round cell tumor differ in their pathology, their clinical behavior, and prognosis.

Spectrum of Renal Tumors Other Than Renal Cell Carcinoma with Emphasis on Cytomorphological, Immunohistochemical, and Cytogenetic Study

Abstract Background: The role of fine needle aspiration cytology (FNAC) in the diagnosis of renal malignancies is established and has been getting more precise and important over a period of time. Knowledge of the pathology of uncommon renal neoplasms along with radiological and clinical correlations often aids in correct diagnosis. Aims: The present study aims to describe the cytomorphological and immunohistochemical findings in the varied spectrum of renal tumors, other than renal cell carcinomas (RCC). Materials and Methods: Data of 238 cases of ultrasound-guided renal FNAC performed in our tertiary cancer institute over 4 years were collected from the department registry. All nondiagnostic cases and cases diagnosed as RCC were excluded from the study, so 57 cases of renal tumors were reviewed along with the cell blocks and ancillary studies. Results: Out of the 57 cases, 35 cases were primary renal neoplasms, which included renal oncocytoma (3.5%), angiomyolipoma (3.5%), rhabdoid tumor (1.8%), Wilms tumor (28.0%), Ewing sarcoma (3.5%), urothelial carcinoma (8.8%), and small round cell tumor unclassified (12.3%). Twenty two cases were metastatic tumors, which included hematolymphoid neoplasm (14%) and metastatic carcinomas (24.6%) from various other primary carcinomas. Conclusion: Our study shows that renal FNAC is safe and fairly accurate in diagnosing a wide spectrum of renal tumors and has high diagnostic accuracy, when performed along with cell block and immunohistochemistry. Awareness of the pathology of uncommon renal tumors along with relevant clinical history and radiological findings may aid in identifying the type of tumor for further appropriate management.

Unusual Presentation of Myeloid Sarcoma as Thigh Mass

IntroductionMyeloid sarcoma (MS) is a tumor containing myeloid blasts, with or without maturation, involving any anatomical site other than the bone marrow. It can occur de novo or following a hematological malignancy. CaseWe report a 6-year-old female who presented with fever and a rapidly enlarging left thigh mass. The initial provisional diagnosis considered was tubercular hip arthritis with an abscess, but imaging investigations suggested neoplastic swelling. A biopsy of the mass showed a malignant small-round cell tumor. Bone marrow aspiration revealed the diagnosis of acute myeloid leukemia without the presence of blasts in the peripheral smear. ConclusionMS is a rare malignancy. The diagnosis is often delayed due to a lack of clinical suspicion and the absence of blasts in peripheral blood. This report aims to enhance the awareness of pediatric nurse practitioners that MS should also be considered as a differential for an extremity mass.

Ewing’s Sarcoma Presenting in the Paranasal Sinus – A Case Report

Abstract Rationale: The aim of this study is to raise awareness among dentists regarding a potential outcome associated with the rapid growth of facial swellings. Patient Concerns: We present a case of Ewing’s sarcoma (ES) in a 23-year-old male who presented with a rapidly progressive swelling in the left maxillary region over six weeks. Diagnosis: There was no significant intraoral dental finding other than a missing left upper first molar. Panoramic imaging initially suggested chronic sinusitis, but the swelling persisted despite treatment. A subsequent cone-beam computed tomography (CBCT) scan revealed a soft-tissue tumour affecting multiple sinuses, confirmed by an open biopsy as a small round cell tumour. Immunohistochemistry was used for precise diagnosis due to biopsy sample limitations and tumour variability. Treatment: The patient’s case was reviewed by our institution’s tumour board. One month after diagnosis, chemotherapy began with alternating drugs for a total of 6 cycles. Outcomes: A follow-up Positron Emission Tomography (PET)/Computed Tomography (CT) scan after two months of chemotherapy showed resolution of the hypermetabolic mass on the left side without evidence of metastatic disease. The patient is currently under regular follow-up. Take-Away Lessons: Dentists should be vigilant for rapidly expanding oral or facial swellings. Early and accurate diagnosis can improve clinical management and survival rates for ES patients.

1784TiP Pasireotide as maintenance treatment in SSTR2/3/5-expressing synovial sarcoma and desmoplastic small round cell tumor: The PAMSARC study

1784TiP Pasireotide as maintenance treatment in SSTR2/3/5-expressing synovial sarcoma and desmoplastic small round cell tumor: The PAMSARC study

EWS-WT1 fusion isoforms establish oncogenic programs and therapeutic vulnerabilities in desmoplastic small round cell tumors

EWS fusion oncoproteins underlie several human malignancies including Desmoplastic Small Round Cell Tumor (DSRCT), an aggressive cancer driven by EWS-WT1 fusion proteins. Here we combine chromatin occupancy and 3D profiles to identify EWS-WT1-dependent gene regulation networks and target genes. We show that EWS-WT1 is a powerful chromatin activator controlling an oncogenic gene expression program that characterizes primary tumors. Similar to wild type WT1, EWS-WT1 has two isoforms that differ in their DNA binding domain and we find that they have distinct DNA binding profiles and are both required to generate viable tumors that resemble primary DSRCT. Finally, we identify candidate EWS-WT1 target genes with potential therapeutic implications, including CCND1, whose inhibition by the clinically-approved drug Palbociclib leads to marked tumor burden decrease in DSRCT PDXs in vivo. Taken together, our studies identify gene regulation programs and therapeutic vulnerabilities in DSRCT and provide a mechanistic understanding of the complex oncogenic activity of EWS-WT1.

Immunohistochemical Evaluation of Schlafen 11 (SLFN11) Expression in Cancer in the Search of Biomarker-Informed Treatment Targets: A Study of 127 Entities Represented by 6658 Tumors.

Schlafen 11 (SLFN11), a DNA/RNA helicase, acts as a regulator of cellular response to replicative stress and irreversibly triggers replication block and cell death. Several preclinical in vitro studies and clinical trials established that SLFN11 expression predicts outcomes in patients with advanced cancer treated with DNA-damaging chemotherapeutics and more recently with poly(ADP-ribose) polymerase inhibitors. SLFN11 expression status remains unknown in many cancer types, especially in mesenchymal tumors. This study evaluated a cohort of well characterized 3808 epithelial and 2850 mesenchymal and neuroectodermal tumors for SLFN11 expression using immunohistochemistry. Nuclear SLFN11 expression was rare in some of the most common carcinomas, for example, hepatocellular (1%), prostatic (2%), colorectal (5%), or breast (16%) cancers. In contrast, other epithelial tumors including mesotheliomas (92%), clear cell renal cell carcinomas (79%), small cell lung cancers (76%), squamous cell carcinomas of the tonsil (89%) and larynx (71%), or ovarian serous carcinomas (69%) were mostly SLFN11-positive. Compared with epithelial malignancies, SLFN11 expression was overall higher in neuroectodermal and mesenchymal tumors. Most positive entities included desmoplastic small round cell tumor (100%), Ewing sarcoma (92%), undifferentiated sarcoma (92%), solitary fibrous tumor (91%), dedifferentiated liposarcoma (89%), synovial sarcoma (86%), and malignant peripheral nerve sheath tumor (85%). Also, this study identifies tumors with potentially worse response to DNA-damaging drugs including antibody drug conjugates due to the absence of SLFN11 expression. Such entities may benefit from alternative treatments or strategies to overcome SLFN11 deficiency-related drug resistance. Our approach and results should serve as a foundation for future biomarker-associated clinical trials.

Surgical management of rare tumors (Part 1).

With an annual cumulative occurrence of approximately 15,000 in North America, all childhood cancers are rare. Very rare cancers as defined by both the European Cooperative Study Group for Rare Pediatric Cancers and the Children's Oncology Group fall into two principal categories: those so uncommon (fewer than 2 cases/million) that their study is challenging even through cooperative group efforts (e.g., pleuropulmonary blastoma and desmoplastic small round cell tumor) and those that are far more common in adults and therefore rarely studied in children (e.g., thyroid, melanoma, and gastrointestinal stromal tumor). Treatment strategies for these latter tumors are typically based on adult guidelines, although the pediatric variants of these tumors may harbor different genetic signatures and demonstrate different behavior. If melanoma and differentiated thyroid cancer are excluded, other rare cancer types account for only 2% of the cancers in children aged 0 to 14. This article highlights several of the most common rare tumor types.

Sinonasal Tumors: Clinical and Morphological Characteristics and Differential Diagnosis

Malignant sinonasal tumors are rare and account for 1% of all neoplasms. Most of these carcinomas are poorly differentiated or undifferentiated tumors. Due to overlapping features, both young and experienced physicians encounter difficulties in their diagnosis. We present 2 cases of 2 tumors of the sinonasal tract, which belong to small round blue cell tumors: sinonasal small cell neuroendocrine tumor and esthesioneuroblastoma.

Novel PAX3::MAML3 Fusion Identified in Alveolar Rhabdomyosarcoma, Using DNA Methylation Profiling to Expand the Genetic Spectrum of “Fusion-Positive” Cases

Alveolar rhabdomyosarcoma (ARMS) with FOXO1 gene rearrangements is an aggressive pediatric rhabdomyosarcoma subtype that is prognostically distinct from embryonal rhabdomyosarcoma and fusion-negative ARMS. Here, we report 2 cases of ARMS with PAX3::MAML3 fusions. The tumors arose in an infant and an adolescent as stage IV metastatic disease (by Children’s Oncology Group staging system). Histologically, both cases were small round blue cell tumors arranged in vague nests and solid sheets that were diffusely positive for desmin and myogenin. By methylation profiling and unsupervised clustering analysis, the tumors clustered with ARMS with classic FOXO1 rearrangements and ARMS with variant PAX3::NCOA1/INO80D fusions, but not with biphenotypic sinonasal sarcoma (BSNS) with PAX3::MAML3/NCOA2/FOXO1/YAP1 fusions nor with other small round blue cell tumors, including embryonal rhabdomyosarcoma. The differentially methylated genes between ARMS and BSNS were highly enriched in genes involved in myogenesis, and 21% of these genes overlap with target genes of the PAX3::FOXO1 fusion transcription factor. On follow-up after initiation of vincristine/actinomycin/cyclophosphamide chemotherapy, the tumors showed partial and complete clinical responses, consistent with typical upfront chemotherapy responsiveness of ARMS with the classic FOXO1 rearrangement. We conclude that PAX3::MAML3 is a novel variant fusion of ARMS, which displays a methylation signature distinct from BSNS despite sharing similar PAX3 fusions. These findings highlight the utility of methylation profiling in classifying ARMS with noncanonical fusions.

HER2 Antibody-Drug Conjugates Are Active against Desmoplastic Small Round Cell Tumor.

Desmoplastic small round cell tumor (DSRCT) is a rare but highly aggressive soft tissue sarcoma that arises in the abdominopelvic cavity of young males. Since the discovery of EWSR1::WT1 fusion as the driver of DSRCT, no actionable genomic alterations have been identified, limiting disease management to a combination of surgery, chemotherapy, and radiation, with very poor outcomes. Herein, we evaluated ERBB2/HER2 expression in DSRCT as a therapeutic target. ERBB2/HER2 expression was assessed in clinical samples and patient-derived xenografts (PDX) using RNA sequencing, RT-qPCR, and a newly developed HER2 IHC assay (clone 29D8). Responses to HER2 antibody-drug conjugates (ADC)-trastuzumab deruxtecan (T-DXd) and trastuzumab emtansine-were evaluated in DSRCT PDX, cell line, and organoid models. Drug internalization was demonstrated by live microscopy. Apoptosis was evaluated by Western blotting and caspase activity assays. ERBB2/HER2 was detectable in DSRCT samples from patients and PDXs, with higher sensitivity RNA assays and improved IHC detectability using clone 29D8. Treatment of ERBB2/HER2-expressing DSRCT PDX, cell line, and organoid models with T-DXd or trastuzumab emtansine resulted in tumor regression. This therapeutic response was long-lasting in T-DXd-treated xenografts and was mediated by rapid HER2 ADC complex internalization and cytotoxicity, triggering p53-mediated apoptosis and growth arrest. Xenograft regression was associated with bystander payload effects triggering global tumor niche responses proportional to HER2 status. ERBB2/HER2 is a therapeutic target in DSRCT. HER2 ADCs may represent novel options for managing this exceptionally aggressive sarcoma, possibly fulfilling an urgent and historically unmet need for more effective clinical therapy.