Desmoplastic Small Round Cell Tumor (DSRCT) is a highly aggressive pediatric cancer caused by a reciprocal translocation between chromosomes 11 and 22, leading to the formation of the EWSR1::WT1 oncoprotein. DSRCT presents most commonly in the abdominal and pelvic peritoneum and remains refractory to current treatment regimens which include chemotherapy, radiotherapy, and surgery. As a rare cancer, sample and model availability have been a limiting factor to DSRCT research. However, the establishment of rare tumor banks and novel cell lines have recently propelled critical advances in the understanding of DSRCT biology and the identification of potentially promising targeted therapeutics. Here we review model and dataset availability, current understanding of the EWSR1::WT1 oncogenic mechanism, and promising preclinical therapeutics, some of which are now advancing to clinical trials. We discuss efforts to inhibit critical dependencies including NTRK3, EGFR, and CDK4/6 as well as novel immunotherapy strategies targeting surface markers highly expressed in DSRCT such as B7-H3 or neopeptides either derived from or driven by the fusion oncoprotein. Finally, we discuss the prospect of combination therapies and strategies for prioritizing clinical translation.

A 13-year-old boy was admitted to the hospital with 1-month history of neck pain and a 2-week history of bilateral hip joint pain accompanied by low fever. Positron emission tomography-computed tomography (PET-CT) revealed the presence of a malignant tumor in the left kidney with metastases to the left renal hilum, retroperitoneum, para-aortic lymph nodes, and multiple bone sites throughout the body. Given that the patient\'s left kidney capsule was intact and the boundary with surrounding tissues was clear, left nephrectomy was performed. Postoperative pathological diagnosis showed desmoplastic small round cell tumor (DSRCT) of the left kidney. CAV-VIP alternating chemotherapy was given 20 days after the first stage surgery. After the end of the 6th cycle, the patient underwent surgery again. The tumor in front of the aorta and postcava, the greater omentum, the retroperitoneal lymph nodes and the hepatic hilum lymph nodes, and the visible tumors in the abdomen were removed. CAV-VIP alternating chemotherapy was continued after the second stage surgery. At the end of the 4th cycle of post operation chemotherapy, radiotherapy was started. An abdominal CT scan conducted 11 months after second-stage surgery did not reveal any recurrence of abdominal tumors; however bone metastases persisted. The patient is currently receiving oral targeted therapy with anlotinib while ongoing follow-up continues.

Desmoplastic small round cell tumor (DSRCT) is a high-grade, primitive round cell sarcoma classically associated with prominent desmoplastic stroma, coexpression of keratin and desmin, and a characteristic EWSR1::WT1 gene fusion. DSRCT typically arises in the abdominopelvic cavity of young males with diffuse peritoneal spread and poor overall survival. Although originally considered to be pathognomonic for DSRCT, EWSR1::WT1 gene fusions have recently been detected in rare tumors lacking the characteristic morphologic and immunohistochemical features of DSRCT. Here, we report 3 additional cases of neoplasms other than conventional DSCRCT with EWSR1::WT1 gene fusions that occurred outside the female genital tract. Two occurred in the abdominopelvic cavities of a 27-year-old man and a 12-year-old girl, whereas the third arose in the axillary soft tissue of an 85-year-old man. All cases lacked prominent desmoplastic stroma and were instead solid and cystic with peripheral fibrous pseudocapsules and occasional intervening fibrous septa. Necrosis was either absent (1/3) or rare (2/3), and mitotic activity was low (<1 to 3 per 10 hpf). In immunohistochemical studies, there was expression of smooth muscle actin (3/3) and desmin (3/3), rare to focal reactivity for EMA (2/3), and variable expression of CK AE1/AE3 (1/3). Myogenin and MyoD1 were negative, and C-terminus-specific WT1 was positive in both cases tested (2/2). All 3 tumors followed a more indolent clinical course with 2 cases demonstrating no evidence of disease at 20 and 44 months after resection. The patient from case 3 died of other causes at 14 months with no evidence of recurrence. DNA methylation profiling showed that the 3 cases clustered with DSRCT; however, they demonstrated fewer copy number variations with 2 cases having a flat profile (0% copy number variation). Differential methylation analysis with hierarchical clustering further showed variation between the 3 cases and conventional DSRCT. Although further study is needed, our results, in addition to previous reports, suggest that EWSR1::WT1 gene fusions occur in rare and seemingly distinctive tumors other than conventional DSRCT with indolent behavior. Proper classification of these unusual soft tissue tumors with EWSR1::WT1 gene fusions requires direct correlation with tumor morphology and clinical behavior, which is essential to avoid overtreatment with aggressive chemotherapy.

Desmoplastic small round cell tumor is a very rare and highly aggressive soft tissue sarcoma, usually presenting with multiple intra-abdominal tumors in young males. Patients present with advanced disease and the overall survival is dismal. Multiple studies report relatively favorable outcomes with multimodal treatment consisting of chemotherapy, surgery and radiotherapy. If resection is feasible, complete cytoreductive surgery is the cornerstone of surgical treatment. The benefit of hyperthermic intraperitoneal chemotherapy in addition to cytoreductive surgery is unclear, and few studies have evaluated this option. We sought to identify the role of hyperthermic intraperitoneal chemotherapy in patients with intra-abdominal desmoplastic small round cell tumor. Our review of the available literature revealed no clear survival benefit in performing hyperthermic intraperitoneal chemotherapy after cytoreductive surgery.

Desmoplastic Small Round Cell Tumor (DSRCT) is a rare and aggressive pediatric cancer driven by the EWSR1-WT1 fusion oncogene. Combinations of chemotherapy, radiation and surgery are not curative, and the 5-years survival rate is less than 25%. One potential explanation for refractoriness is the existence of a cancer stem cell (CSC) subpopulation able escape current treatment modalities. However, no study to-date has examined the role of CSCs in DSRCT or established in vitro culture conditions to model this subpopulation. In this study, we investigated the role of stemness markers in DSRCT survival and metastasis, finding that elevated levels of SOX2 and NANOG are associated with worse survival in sarcoma patients and are elevated in metastatic DSRCT tumors. We further develop the first in vitro DSRCT CSC model which forms tumorspheres, expresses increased levels of stemness markers (SOX2, NANOG, KLF4, and OCT4), and resists doxorubicin chemotherapy treatment. This model is an important addition to the DSRCT tool kit and will enable investigation of this critical DSRCT subpopulation. Despite lower sensitivity to chemotherapy, the DSRCT CSC model remained sensitive to knockdown of the EWSR1-WT1 fusion protein, suggesting that future therapies directed against this oncogenic driver have the potential to treat both DSRCT bulk tumor and CSCs.

Primary desmoplastic small round cell tumor (DSRCT) in the head and neck region is extremely rare. There is limited information about its clinicopathological characteristics, prognosis, and treatment modalities. The purpose of this study is to provide a comprehensive review of DSRCT occurring primarily in the head and neck, to demonstrate its peculiar morphology and immunohistochemical expression, and to address the differential diagnoses. A total of 25 cases were collected after a thorough review of the relevant literature. DSRCT was most frequently reported in the major salivary glands, followed by the eyes. Furthermore, some cases were misinterpreted as poorly differentiated carcinoma, Ewing sarcoma, and olfactory neuroblastoma. Diagnosing DSRCTs in the head and neck can be very challenging due to their rarity in this location, overlapping morphology, and immunohistochemistry. In these cases, following a systemic approach helps to solve diagnostic problems.

In the United States, more than 10 000 cancers occur annually in children aged 0-14 years, and more than 5000 in adolescents aged 15-19. In the last 50 years, significant advances have been made in imaging, molecular pathology, stage and risk assessment, surgical approach, multidisciplinary treatment, and survival for pediatric solid tumors (particularly neuroblastoma, Wilms tumor, rhabdomyosarcoma, and hepatoblastoma). Moreover, the molecular driver for fibrolamellar hepatocellular carcinoma, which occurs in adolescence and young adulthood, has been identified.

The incidence and prognosis of desmoplastic small round cell tumor (DSRCT) is inadequately understood. Survival analysis for DSRCT has not been investigated in a population-based study. We conducted a retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER) 9 Registry (1975-2018). Annual percent changes in incidence were estimated using SEER*Stat, and risk ratios were estimated using Poisson regression. Cox regression models were constructed to estimate the hazard ratio for survival at 5 years. The incidence rate of DSRCT has been rising in the last two decades. Men had a higher age-adjusted incidence rate, and nonmetropolitan counties had a higher incidence rate than metropolitan counties. Blacks had a higher risk of being diagnosed with DSRCT than whites. The observed survival at 12, 36, and 60 months was 81%, 39.9%, and 23.4%, respectively. Those >70 years had a poorer survival than those <60 years (P < 0.001). Compared to surgery with chemotherapy, surgery with chemoradiotherapy was linked to a 53% lower risk of mortality (P < 0.001). We conclude that the DSRCT incidence has been increasing since 2000 with a white male predominance. Gender doesn\'t affect survival in DSRCT, and surgery combined with chemoradiotherapy improves survival compared to surgical management with chemotherapy alone.

Desmoplastic small round cell tumor (DSRCT) is a rare malignant tumor that occurs mainly in the retroperitoneum of children and young adults. In its prototypical form, DSCRT displays characteristic morphology with nested primitive small round cells in a desmoplastic stroma and a distinctive immunophenotype with polyphenotypic differentiation. However, DSCRT can also exhibit a broader clinical, histologic and immunohistochemical spectrum and, therefore, cause diagnostic difficulties. Given that DSCRT is an aggressive and nearly universally fatal disease, making the correct diagnosis is critically important. Herein, we report three patients with DSRCT and unusual clinical, morphologic or immunohistochemical characteristics, in order to highlight its remarkable diversity and increase awareness of this unusual, distinctive neoplasm.

Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive soft tissue sarcoma with a lack of effective treatment options and a poor prognosis. DSRCT is characterized by a chromosomal translocation, resulting in the EWSR1-WT1 gene fusion. The molecular mechanisms driving DSRCT are poorly understood, and a paucity of preclinical models hampers DSRCT research. Here, we establish a novel primary patient-derived DSRCT in vitro model, recapitulating the original tumor. We find that EWSR1-WT1 expression affects cell shape and cell survival, and we identify downstream target genes of the EWSR1-WT1 fusion. Additionally, this preclinical in vitro model allows for medium-throughput drug screening. We discover sensitivity to several drugs, including compounds targeting RTKs. MERTK, which has been described as a therapeutic target for several malignancies, correlates with EWSR1-WT1 expression. Inhibition of MERTK with the small-molecule inhibitor UNC2025 results in reduced proliferation of DSRCT cells in vitro, suggesting MERTK as a therapeutic target in DSRCT. This study underscores the usefulness of preclinical in vitro models for studying molecular mechanisms and potential therapeutic options.