Ewing Sarcoma Beyond the Bone A Rare Primary renal presentation care report

Ewing Sarcoma Beyond the Bone A Rare Primary renal presentation care report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Ewing Sarcoma Beyond the Bone A Rare Primary renal presentation care report M. Benkova-Petrova¹, A. Petrov¹, S. Marinov, L. Stoev, M. Hachmerian This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8309965/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Ewing sarcoma is a rare but aggressive malignant tumor that primarily affects adolescents and young adults. Although it typically arises in bone, in rare cases it may originate in parenchymal organs such as the kidney. Case Presentation: We present a 45-year-old woman with a history of breast carcinoma and a right renal mass. Imaging revealed a multicystic lesion with septations and nodular thickening. Histology and immunohistochemistry were consistent with extraskeletal Ewing sarcoma; FISH confirmed the characteristic rearrangement (t(11;22)(q24;q12)/EWSR1-ETS). The patient underwent nephrectomy followed by VDC/IE chemotherapy. Given her oncologic history and age, Li-Fraumeni syndrome was considered. Conclusions: This case highlights a rare primary renal localization of Ewing sarcoma and underscores the value of a multidisciplinary approach with molecular confirmation to secure diagnosis and guide therapy. Ewing sarcoma primary renal extraskeletal tumor EWSR1 rearrangement FISH analysis nephrectomy VDC/IE Li-Fraumeni syndrome case report Figures Figure 1 Figure 2 Figure 3 1. Introduction Primary renal Ewing sarcoma (ES) is exceptional in adults and easily mimics other renal “small round blue cell” neoplasms. This report documents a small (28×23×27 mm) renal ES in a 45-year-old woman, with full morphology-IHC-FISH concordance and standard VDC/IE management, and a clinical context suggestive of Li-Fraumeni. Ewing sarcoma is an aggressive malignant tumor that predominantly affects adolescents and young adults, accounting for 10–15% of all bone sarcomas [ 1 ]. The disease was first described by James Ewing in 1921. Under the umbrella term “Ewing sarcoma” are included classic osseous Ewing sarcoma, extraskeletal Ewing sarcoma, the malignant small round cell tumor of the chest wall (Askin tumor), and primitive neuroectodermal tumors of soft tissue origin. All share a common origin from unique mesenchymal progenitor cells, due to their overlapping histological and immunohistochemical features [ 2 ]. The most frequently affected anatomical sites are the pelvis, axial skeleton, and femur, although Ewing sarcoma can develop in virtually any bone or soft tissue. Patients typically present with local symptoms such as pain, stiffness, or swelling, often persisting for weeks or months. More than 50% report intermittent pain that worsens at night. The tumor most often arises in the diaphysis of long bones, but other locations can lead to diverse clinical presentations. In cases with osseous or metastatic lesions, pathological fractures may occur. Pelvic localization often presents with back pain. Systemic manifestations such as fever and weight loss usually indicate metastatic disease. Approximately 20% of patients are diagnosed at a metastatic stage, with more than 20% showing lung or pleural involvement [ 2 ]. The incidence of extraskeletal Ewing sarcoma is 0.4 per million, ten times less frequent than osseous Ewing sarcoma [ 3 ]. Its distribution follows a bimodal pattern, with peaks in children under 5 years of age and adults over 35 years [ 4 ]. Extraskeletal sites include the paravertebral region, lower extremities, head, neck, and pelvis [ 5 ]. Rarer locations are the retroperitoneum, omentum, orbit, skin, and chest wall [ 6 ]. These tumors more commonly arise in axial regions and less often in the pelvis [ 6 ]. Secondary involvement of adjacent bone is rare, even when the mass is located near osseous structures. Ewing sarcoma family tumors are characterized by chromosomal translocations resulting in fusion genes that encode aberrant transcription factors. The translocation t(11;22)(q24;q12) is present in approximately 85% of cases, producing the EWS-FLI1 fusion gene, while t(21;22)(q21;q12) and other rarer rearrangements result in EWS-ERG fusions observed in 10–15% of cases [ 7 ]. The resulting EWSR1-FLI1 oncoprotein is considered both necessary and sufficient for tumorigenesis [ 8 , 9 ]. Consequently, inhibiting this protein is a desirable therapeutic goal, although not essential clinically, as evidenced by the effectiveness of non-targeted chemotherapy in many patients with localized disease [ 8 , 9 ]. Histologically, Ewing sarcoma consists of small, round cells with a high nuclear-to-cytoplasmic ratio, belonging to the group of “small round blue cell tumors” of childhood, along with retinoblastoma, neuroblastoma, rhabdomyosarcoma, and nephroblastoma. The cells have scant eosinophilic cytoplasm rich in glycogen, often highlighted by periodic acid-Schiff (PAS) staining [ 7 ]. More than 80% of cases exhibit strong CD99 expression. Although this highly sensitive immunohistochemical marker may play a role in leukocyte-endothelial adhesion, it is not specific, as positivity is also seen in other sarcomas and lymphomas [ 7 ]. In addition to CD99 (MIC2 gene product), Ewing sarcoma cells often express markers such as CD45, synaptophysin, chromogranin, vimentin, keratin, desmin, neuron-specific enolase, and S-100. However, this panel has limited diagnostic specificity [ 7 ]. Definitive diagnosis requires molecular techniques such as fluorescence in situ hybridization (FISH) or RT-PCR. Integrating histopathological and immunohistochemical findings with appropriate clinical context helps narrow the differential diagnosis of Ewing sarcoma. The main differential diagnoses include other small round cell malignancies such as neuroblastoma, rhabdomyosarcoma, lymphoma, desmoplastic small round cell tumor, and synovial sarcoma. Benign conditions such as osteomyelitis, osteogenic sarcoma, and eosinophilic granuloma should also be considered. Initial imaging usually involves radiography of the affected area, which may demonstrate the characteristic periosteal “onion-skin” reaction [ 10 ]. For staging, bone scintigraphy, MRI, and CT are essential. The current treatment standard, both in localized and metastatic disease, requires an interdisciplinary approach combining chemotherapy with local therapy-surgery, radiotherapy, or both. Systemic therapy remains the cornerstone of management. In the United States, the standard protocol alternates VDC (vincristine/doxorubicin/cyclophosphamide) with IE (ifosfamide/etoposide) [ 11 ]. After induction chemotherapy, local control is usually pursued with surgery, radiotherapy, or their combination. In patients with non-metastatic disease, 5-year survival rates range between 75% and 80%, whereas in metastatic cases survival drops to about 30% [ 12 , 13 ]. Over the last four decades, significant progress has been made in treating localized Ewing sarcoma with local therapy and multi-agent adjuvant chemotherapy. However, prognosis remains poor for metastatic disease, diagnosed in 20–25% of patients (primarily lung metastases in 70–80% and bone/bone marrow in 40–45%) [ 14 , 12 ]. Moreover, relapse occurs in 30–40% of patients initially diagnosed with localized disease, rising to 60–80% in those with metastases at presentation. Relapses are most often systemic (71–73%), followed by combined (12–18%) and local (11–15%). Five-year survival after relapse is only 15–25%, with local recurrences carrying a better prognosis than systemic ones [ 15 – 17 ]. Controlling systemic tumor dissemination remains the main therapeutic challenge. 2. Case Presentation We present the case of a 45-year-old woman with a history of breast carcinoma, treated by right-sided mastectomy in 2015. In early 2023, she reported new complaints of right lumbar pain, reduced physical capacity, and recurrent episodes of painless gross hematuria. Initial imaging with ultrasound followed by magnetic resonance imaging (MRI) revealed a well-demarcated lesion in the mid-portion of the right kidney, measuring 28 × 23 × 27 mm. The lesion protruded along the dorsal contour of the kidney and demonstrated a multicystic architecture with multiple septations, some irregular in course, with areas of nodular thickening up to 3–4 mm. On T2-weighted MRI sequences, the lesion displayed mixed signal intensity, predominantly hyperintense, while the septa were markedly hypointense. The possibility of intralesional hemorrhage with hemoglobin degradation products was considered. No distant metastases were detected during staging. In October 2023, the patient was admitted to the Clinic of Urology, University Hospital “St. Marina,” Varna, where partial resection of the renal tumor was performed. Histopathology. The lesion was composed of monotonous tumor cells with scant, clear cytoplasm and round-to-oval nuclei lacking prominent nucleoli. The cells formed solid nests and Homer-Wright rosettes. Scattered foci of necrosis and numerous apoptotic bodies were observed. Mitotic activity was 5/10 HPF. PAS highlighted cytoplasmic glycogen granules. Immunohistochemistry. The immunophenotype showed positivity for CD99, Cyclin D1, WT1, vimentin, S100, p53 (~ 50%), and synaptophysin (~ 30%); negative for CD117, CD10, inhibin, CK7, GATA3, CD34, SMA, CK AE1/AE3, HMB45, Melan-A. Ki-67 ~ 15%. The morphological and immunohistochemical findings were most consistent with extraskeletal Ewing sarcoma. To confirm this diagnosis, molecular genetic analysis was performed on formalin-fixed tumor tissue at an external reference laboratory (Eurofins Biomnis Lyon, France). FISH (break-apart) demonstrated EWSR1 gene rearrangement in 100% of 100 nuclei. The differential diagnosis included other members of the “small round blue cell tumor” family, such as Wilms tumor, neuroblastoma, clear cell sarcoma of the kidney, and lymphoma. Based on the combined histological, immunohistochemical, and molecular findings, the final diagnosis of primary renal extraskeletal Ewing sarcoma was established. Following diagnostic confirmation, the patient underwent right nephrectomy at a specialized clinic in Austria, followed by systemic chemotherapy according to the VDC/IE protocol (vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide and etoposide). Given the previous diagnosis of breast carcinoma at age 37 and the present diagnosis of a second malignant neoplasm at age 45, medical genetic counseling was undertaken to evaluate the possibility of Li-Fraumeni syndrome (germline TP53). The patient declined genetic testing. 3. Discussion The first documented case of renal Ewing sarcoma was reported in 1975 [ 18 ]. Clinical manifestations are often nonspecific, with patients most commonly presenting with pain and a palpable mass [ 19 , 20 ]. Due to its inherently aggressive nature, renal ES may present with advanced disease and early metastases [ 21 ]. The definitive diagnosis relies on histopathological examination combined with immunohistochemistry. Ewing sarcoma belongs to the group of “small round blue cell tumors.” Histologically, the differential diagnosis must first consider other neoplasms within this category, including Wilms tumor, neuroblastoma, clear cell sarcoma of the kidney, desmoplastic small round cell tumor, lymphoma, small-cell variant of osteosarcoma, and neuroendocrine tumors [ 22 ]. Characteristic morphological features such as Homer-Wright rosettes and diffuse, strong CD99 expression are highly suggestive, yet the gold standard for confirmation remains molecular proof of EWSR1-ETS rearrangement by FISH/RT-PCR/NGS [ 23 ]. In the present case, the lesion exhibited the classical morphology and immunohistochemical profile, with FISH confirmation. Given the exceptional rarity of primary renal ES, there is no established therapeutic protocol specifically tailored to this localization. Treatment strategies are therefore extrapolated from those used for osseous ES. Successful management requires a multimodal approach, combining surgery, chemotherapy, and radiotherapy [ 19 ]. The most commonly used chemotherapy regimen consists of VDC/IE [ 20 ]. Most reported cases describe radical nephrectomy as the preferred surgical intervention, although nephron-sparing procedures have occasionally been performed [ 24 , 25 ]. Renal ES is considered more aggressive than tumors arising in other locations, with a high propensity for local recurrence and early metastasis to lymph nodes, lungs, liver, and bone [ 26 ]. This confers a poorer prognosis compared with classic osseous ES. Broader ES cohorts highlight high relapse rates and the need for vigilant surveillance [ 12 – 17 ]. 4. Conclusions This case illustrates a rare extraskeletal ES with primary renal localization. The diagnostic process required integrated imaging, histopathology, immunohistochemistry, and molecular confirmation (EWSR1 rearrangement). Surgical intervention followed by VDC/IE chemotherapy provided disease control. The patient’s oncologic history raised the suspicion of Li-Fraumeni; genetic testing was declined. Awareness, interdisciplinary collaboration, and personalized strategies remain critical. Abbreviations ES - Ewing sarcoma PNET - Primitive neuroectodermal tumor MRI - Magnetic resonance imaging CT - Computed tomography IHC - Immunohistochemistry FISH - Fluorescence in situ hybridization PAS - Periodic acid–Schiff HPF - High-power field VDC/IE - Vincristine, doxorubicin, cyclophosphamide / Ifosfamide, etoposide NGS - Next-generation sequencing Declarations Author Contributions Conceptualization, M.B.-P. and A.P.; Investigation, M.B.-P., S.S., L.S., M.H., D.A., and A.P.; Data Curation, M.B.-P. and L.S.; Writing-Original Draft, M.B.-P.; Writing-Review & Editing, A.P., S.S., L.S., M.H., and D.A.; Supervision, A.P. Funding This research received no external funding. Ethical considerations and approval: Ethical approval was waived by the Ethics Committee of University Hospital “St. Marina”, Varna, as this study represents a single-patient case report with no experimental intervention beyond standard clinical care, in accordance with institutional and national ethical guidelines. Accordance with ethical guidelines All procedures involving human participants were performed in accordance with institutional ethical standards and with the principles of the Declaration of Helsinki. Consent to participate Written informed consent to participate in the study was obtained from the patient. Consent to publish Written informed consent for publication of clinical details and images was obtained from the patient. Data availability statement Data sharing not applicable to this article as no datasets were generated or analysed during the current study. Institutional Review Board Statement Ethical review and approval were waived for this single-patient case report according to local regulations; no experimental intervention beyond standard care was performed. Data Availability Statement No new data were created or analyzed in this study; data sharing is not applicable. Acknowledgments We thank the clinical staff involved in patient management and the collaborating pathology, urology, and medical genetics teams; we especially thank the patient for consenting to publication. Conflicts of Interest The authors declare no conflicts of interest. Ethical approval: The study protocol was approved by the Ethics Committee of University Hospital “St. Marina”, Varna, and all methods were performed in accordance with relevant guidelines and regulations. Consent to participate: Written informed consent to participate was obtained from the patient. Consent to publish: Written informed consent for publication of clinical details and images was obtained from the patient. References Ludwig JA. Ewing sarcoma: historical perspectives, current state-of-the-art, and opportunities for targeted therapy in the future. Curr Opin Oncol. 2008;20(4):412-418. Ozaki T. Diagnosis and treatment of Ewing sarcoma of the bone: a review article. J Orthop Sci. 2015;20(2):250-263. Van den Berg H, Heinen RC, van der Pal HJ, Merks JH. Extra-osseous Ewing sarcoma. Pediatr Hematol Oncol. 2009;26:175-185. doi:10.1080/08880010902855581. Applebaum MA, Worch J, Matthay KK, et al. Clinical features and outcomes in patients with extraskeletal Ewing sarcoma. Cancer. 2011;117:3027-3032. doi:10.1002/cncr.25840. Cheung CC, Kandel RA, Bell RS, Mathews RE, Ghazarian MD. Extraskeletal Ewing sarcoma in a 77-year-old woman. Arch Pathol Lab Med. 2001;125:1358-1360. doi:10.5858/2001-125-1358-EESIAY. Geens L, Van Robays J, Geert V, Van der Speeten K. An unusual location of extraosseous Ewing’s sarcoma. Case Rep Oncol. 2013;6:293-302. doi:10.1159/000351836. Riggi N, Stamenkovic I. The biology of Ewing sarcoma. Cancer Lett. 2007;254(1):1-10. Kovar H, Aryee DN, Jug G, et al. EWS/FLI-1 antagonists induce growth inhibition of Ewing tumor cells in vitro . Cell Growth Differ. 1996;7:429-437. Lambert G, Bertrand JR, Fattal E, et al. EWS-FLI1 antisense nanocapsules inhibit Ewing sarcoma-related tumor in mice. Biochem Biophys Res Commun. 2000;279:401-406. doi:10.1006/bbrc.2000.3963. Widhe B, Widhe T. Initial symptoms and clinical features in osteosarcoma and Ewing sarcoma. J Bone Joint Surg Am. 2000;82(5):667-674. Grier HE, Krailo MD, Tarbell NJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and PNET of bone. N Engl J Med. 2003;348(8):694-701. Ladenstein R, Potschger U, Le Deley MC, et al. Primary disseminated multifocal Ewing sarcoma: Euro-EWING 99 results. J Clin Oncol. 2010;28:3284-3291. doi:10.1200/JCO.2009.22.9864. Leavey PJ, Collier AB. Ewing sarcoma: prognostic criteria, outcomes and future treatment. Expert Rev Anticancer Ther. 2008;8(4):617-624. Haeusler J, Ranft A, Boelling T, et al. The value of local treatment in patients with primary, disseminated, multifocal ES (PDMES). Cancer. 2010;116:443-450. doi:10.1002/cncr.24740. Barker LM, Pendergrass TW, Sanders JE, Hawkins DS. Survival after recurrence of Ewing’s sarcoma family of tumors. J Clin Oncol. 2005;23:4354-4362. doi:10.1200/JCO.2005.05.105. Rodriguez-Galindo C, Billups CA, Kun LE, et al. Survival after recurrence of Ewing tumors: St. Jude experience, 1979–1999. Cancer. 2002;94:561-569. doi:10.1002/cncr.10192. Stahl M, Ranft A, Paulussen M, et al. Risk of recurrence and survival after relapse in patients with ES. Pediatr Blood Cancer. 2011;57:549-553. doi:10.1002/pbc.23040. Seemayer TA, Thelmo WL, Bolande RP, Wiglesworth FW. Peripheral neuroectodermal tumors. Perspect Pediatr Pathol. 1975;2:151-172. Ellinger J, Bastian PJ, Hauser S, Biermann K, Müller SC. Primitive neuroectodermal tumor: rare, highly aggressive differential diagnosis in urologic malignancies. Urology. 2006;68:257-262. doi:10.1016/j.urology.2006.02.037. Tarek N, Said R, Andersen CR, et al. Primary renal ES/PNET: MD Anderson experience. Cancers (Basel). 2020;12:2927. doi:10.3390/cancers12102927. Almeida MF, Patnana M, Korivi BR, Kalhor N, Marcal L. Ewing sarcoma of the kidney: a rare entity. Case Rep Radiol. 2014;2014:283902. doi:10.1155/2014/283902. Doroudinia A, Ahmadi S, Mehrian P, Pourabdollah M. Primary Ewing sarcoma of the kidney. BMJ Case Rep. 2019;12(1):bcr-2018-227198. doi:10.1136/bcr-2018-227198. Yoshida A. Ewing and Ewing-like sarcomas: a morphological guide through genetically-defined entities. Pathology International. doi:10.1111/pin.13293. Suzuki I, Kubota M, Murata S, et al. A case of ES family tumor of the kidney treated with robotic-assisted partial nephrectomy. Urol Case Rep. 2019;25:100900. doi:10.1016/j.eucr.2019.100900. Hakky TS, Gonzalvo AA, Lockhart JL, Rodriguez AR. Primary renal ES: symptomatic presentation and literature review. Ther Adv Urol. 2013;5:153-159. doi:10.1177/1756287212471095. Parham DM, Roloson GJ, Feely M, Green DM, Bridge JA, Beckwith JB. Primary malignant neuroepithelial tumors of the kidney: analysis of 146 cases. Am J Surg Pathol. 2001;25:133-146. doi:10.1097/00000478-200102000-00001. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8309965","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":568990079,"identity":"bfea891d-f55d-4911-ba98-41a20159d33e","order_by":0,"name":"M. Benkova-Petrova¹","email":"","orcid":"","institution":"Medical University “Prof. Dr. Paraskev Stoyanov” – Varna","correspondingAuthor":false,"prefix":"","firstName":"M.","middleName":"","lastName":"Benkova-Petrova¹","suffix":""},{"id":568990080,"identity":"9d8b786c-3342-4a45-8f5a-0d79481b23df","order_by":1,"name":"A. Petrov¹","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABIElEQVRIiWNgGAWjYDACdjDJjBBgY28AkgYWuLUwI2s5AMR8PCDSQIIELXISCSAmbi38zczHJH7usJYzb+A9+PjjHpvENsnnVzf8KJBg4G/vTsCmReIwW7Jh75l0Y5kDfMkGB56lJbZJ55Td7AE6TOLM2Q1YrTnMY/iAt+1w4gwGHjOJAwcOG7NJ56Td4AFqMZDIxapF/jD/h4N/2w7XA7WY/wBrkTyTdvMPHi0Gh3kYHwNtSZAA2sIA1CLHJsF+7DY+WwwPsxkby7alG85g5kuWOHMgTY6NJ4fttoyBBA8uv8gdb34m+bbNWl6Cvffgh4oDNjzy7cef3Xzzx0aOv70Xu/fhgJkHxuIxAJP4lTOgqGF/QITqUTAKRsEoGEEAAHdfXO7UjC36AAAAAElFTkSuQmCC","orcid":"","institution":"Medical University “Prof. Dr. Paraskev Stoyanov” – Varna","correspondingAuthor":true,"prefix":"","firstName":"A.","middleName":"","lastName":"Petrov¹","suffix":""},{"id":568990081,"identity":"2dae6ee7-d410-48f4-8900-e43415b0578a","order_by":2,"name":"S. Marinov","email":"","orcid":"","institution":"University Hospital “St. Marina” EAD","correspondingAuthor":false,"prefix":"","firstName":"S.","middleName":"","lastName":"Marinov","suffix":""},{"id":568990082,"identity":"de71024f-fc60-4be7-80f7-8123db271593","order_by":3,"name":"L. Stoev","email":"","orcid":"","institution":"University Hospital “St. Marina” EAD","correspondingAuthor":false,"prefix":"","firstName":"L.","middleName":"","lastName":"Stoev","suffix":""},{"id":568990083,"identity":"0c204b82-52cf-472f-9f86-a8def1806d9f","order_by":4,"name":"M. Hachmerian","email":"","orcid":"","institution":"University Hospital “St. Marina” EAD","correspondingAuthor":false,"prefix":"","firstName":"M.","middleName":"","lastName":"Hachmerian","suffix":""}],"badges":[],"createdAt":"2025-12-08 17:08:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8309965/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8309965/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":99495495,"identity":"79a422e7-b7c7-4831-9c2a-ed17ba92af1a","added_by":"auto","created_at":"2026-01-05 06:17:03","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":2456601,"visible":true,"origin":"","legend":"","description":"","filename":"EWINGkidney.docx","url":"https://assets-eu.researchsquare.com/files/rs-8309965/v1/743e6ec79b00524611c14c4d.docx"},{"id":99495489,"identity":"b27daf8c-bdd4-461e-b182-bd0d4547069a","added_by":"auto","created_at":"2026-01-05 06:17:02","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":5853,"visible":true,"origin":"","legend":"","description":"","filename":"b1563e25bde74c9e8c62a2954100db0e.json","url":"https://assets-eu.researchsquare.com/files/rs-8309965/v1/52d281456e20389c9f935ec2.json"},{"id":99790200,"identity":"2d2fb4b6-f17e-405d-aaed-dfa07357a06b","added_by":"auto","created_at":"2026-01-08 12:57:15","extension":"xml","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":64978,"visible":true,"origin":"","legend":"","description":"","filename":"b1563e25bde74c9e8c62a2954100db0e1enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-8309965/v1/c7ce3cd4fb00d25f2a507181.xml"},{"id":99791152,"identity":"74b501ba-5f63-489f-bd49-2984d76271bf","added_by":"auto","created_at":"2026-01-08 12:59:12","extension":"jpeg","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":485444,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8309965/v1/91ab94e93e308ab7a453c636.jpeg"},{"id":99791159,"identity":"77e7a3b3-48b6-4492-b165-b7100b1ce999","added_by":"auto","created_at":"2026-01-08 12:59:12","extension":"jpeg","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":699692,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8309965/v1/c18f722f9a22748b7a209370.jpeg"},{"id":99495501,"identity":"854cc134-6353-4a09-9b0b-e589f701ae0d","added_by":"auto","created_at":"2026-01-05 06:17:03","extension":"png","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1107269,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8309965/v1/9c03aa77ad2f4cdd741a29d6.png"},{"id":99495496,"identity":"af025e5e-a203-4568-9df9-d9a1d8e569ce","added_by":"auto","created_at":"2026-01-05 06:17:03","extension":"png","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":180770,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8309965/v1/3893d46c9bffe3ce89499d8c.png"},{"id":99495497,"identity":"f1d423a1-1321-4a3e-9187-b0b5f4b0f5ca","added_by":"auto","created_at":"2026-01-05 06:17:03","extension":"png","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":137825,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8309965/v1/64a2a31770023575a2f90656.png"},{"id":99790126,"identity":"4af8beae-a34d-4898-baec-d4c562a636bb","added_by":"auto","created_at":"2026-01-08 12:56:30","extension":"png","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":136414,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8309965/v1/e2495197cc5c1398c8eb2f62.png"},{"id":99790243,"identity":"eee39c0a-bc1d-4ced-9823-d379ba0315e6","added_by":"auto","created_at":"2026-01-08 12:57:30","extension":"xml","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":63240,"visible":true,"origin":"","legend":"","description":"","filename":"b1563e25bde74c9e8c62a2954100db0e1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8309965/v1/cb28e875c508a5c0c84b1942.xml"},{"id":99495500,"identity":"8224749d-35b5-4517-8ff6-3eaf63edbdf9","added_by":"auto","created_at":"2026-01-05 06:17:03","extension":"html","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":73190,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8309965/v1/f74d29e27f46d0194af32155.html"},{"id":99791409,"identity":"41b00fc1-b084-4cff-800a-8f21039f6beb","added_by":"auto","created_at":"2026-01-08 12:59:44","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":248981,"visible":true,"origin":"","legend":"\u003cp\u003eAxial T2-weighted MRI: well-demarcated multicystic right renal lesion with septations and nodular thickening (scale bar shown).\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8309965/v1/38ac15d4709f9695b7b1fd31.jpeg"},{"id":99495487,"identity":"eff4756e-c38e-45a8-9aff-404e335041e5","added_by":"auto","created_at":"2026-01-05 06:17:02","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":374968,"visible":true,"origin":"","legend":"\u003cp\u003eCoronal T2-weighted MRI: dorsal protrusion and mixed T2 signal; hypointense septa.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8309965/v1/c8c0299a695828efce39c6e7.jpeg"},{"id":99790549,"identity":"89d0c302-476b-4c66-9e84-479054becab3","added_by":"auto","created_at":"2026-01-08 12:58:19","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":850735,"visible":true,"origin":"","legend":"\u003cp\u003eHistology, H\u0026amp;E ×400: sheets of small round cells with Homer-Wright rosettes.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8309965/v1/cfd9104fe5ccb57a98a40398.png"},{"id":107705158,"identity":"17c6f370-3b1b-4125-885e-276ee63ad821","added_by":"auto","created_at":"2026-04-24 09:08:43","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1825863,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8309965/v1/a18e875e-b098-4111-9874-c49f36cd0726.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Ewing Sarcoma Beyond the Bone A Rare Primary renal presentation care report","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003ePrimary renal Ewing sarcoma (ES) is exceptional in adults and easily mimics other renal \u0026ldquo;small round blue cell\u0026rdquo; neoplasms. This report documents a small (28\u0026times;23\u0026times;27 mm) renal ES in a 45-year-old woman, with full morphology-IHC-FISH concordance and standard VDC/IE management, and a clinical context suggestive of Li-Fraumeni.\u003c/p\u003e \u003cp\u003eEwing sarcoma is an aggressive malignant tumor that predominantly affects adolescents and young adults, accounting for 10\u0026ndash;15% of all bone sarcomas [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The disease was first described by James Ewing in 1921. Under the umbrella term \u0026ldquo;Ewing sarcoma\u0026rdquo; are included classic osseous Ewing sarcoma, extraskeletal Ewing sarcoma, the malignant small round cell tumor of the chest wall (Askin tumor), and primitive neuroectodermal tumors of soft tissue origin. All share a common origin from unique mesenchymal progenitor cells, due to their overlapping histological and immunohistochemical features [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe most frequently affected anatomical sites are the pelvis, axial skeleton, and femur, although Ewing sarcoma can develop in virtually any bone or soft tissue. Patients typically present with local symptoms such as pain, stiffness, or swelling, often persisting for weeks or months. More than 50% report intermittent pain that worsens at night. The tumor most often arises in the diaphysis of long bones, but other locations can lead to diverse clinical presentations. In cases with osseous or metastatic lesions, pathological fractures may occur. Pelvic localization often presents with back pain. Systemic manifestations such as fever and weight loss usually indicate metastatic disease. Approximately 20% of patients are diagnosed at a metastatic stage, with more than 20% showing lung or pleural involvement [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe incidence of extraskeletal Ewing sarcoma is 0.4 per million, ten times less frequent than osseous Ewing sarcoma [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Its distribution follows a bimodal pattern, with peaks in children under 5 years of age and adults over 35 years [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Extraskeletal sites include the paravertebral region, lower extremities, head, neck, and pelvis [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Rarer locations are the retroperitoneum, omentum, orbit, skin, and chest wall [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. These tumors more commonly arise in axial regions and less often in the pelvis [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Secondary involvement of adjacent bone is rare, even when the mass is located near osseous structures.\u003c/p\u003e \u003cp\u003eEwing sarcoma family tumors are characterized by chromosomal translocations resulting in fusion genes that encode aberrant transcription factors. The translocation t(11;22)(q24;q12) is present in approximately 85% of cases, producing the EWS-FLI1 fusion gene, while t(21;22)(q21;q12) and other rarer rearrangements result in EWS-ERG fusions observed in 10\u0026ndash;15% of cases [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The resulting EWSR1-FLI1 oncoprotein is considered both necessary and sufficient for tumorigenesis [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Consequently, inhibiting this protein is a desirable therapeutic goal, although not essential clinically, as evidenced by the effectiveness of non-targeted chemotherapy in many patients with localized disease [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHistologically, Ewing sarcoma consists of small, round cells with a high nuclear-to-cytoplasmic ratio, belonging to the group of \u0026ldquo;small round blue cell tumors\u0026rdquo; of childhood, along with retinoblastoma, neuroblastoma, rhabdomyosarcoma, and nephroblastoma. The cells have scant eosinophilic cytoplasm rich in glycogen, often highlighted by periodic acid-Schiff (PAS) staining [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMore than 80% of cases exhibit strong CD99 expression. Although this highly sensitive immunohistochemical marker may play a role in leukocyte-endothelial adhesion, it is not specific, as positivity is also seen in other sarcomas and lymphomas [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In addition to CD99 (MIC2 gene product), Ewing sarcoma cells often express markers such as CD45, synaptophysin, chromogranin, vimentin, keratin, desmin, neuron-specific enolase, and S-100. However, this panel has limited diagnostic specificity [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Definitive diagnosis requires molecular techniques such as fluorescence in situ hybridization (FISH) or RT-PCR.\u003c/p\u003e \u003cp\u003eIntegrating histopathological and immunohistochemical findings with appropriate clinical context helps narrow the differential diagnosis of Ewing sarcoma. The main differential diagnoses include other small round cell malignancies such as neuroblastoma, rhabdomyosarcoma, lymphoma, desmoplastic small round cell tumor, and synovial sarcoma. Benign conditions such as osteomyelitis, osteogenic sarcoma, and eosinophilic granuloma should also be considered.\u003c/p\u003e \u003cp\u003eInitial imaging usually involves radiography of the affected area, which may demonstrate the characteristic periosteal \u0026ldquo;onion-skin\u0026rdquo; reaction [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. For staging, bone scintigraphy, MRI, and CT are essential.\u003c/p\u003e \u003cp\u003eThe current treatment standard, both in localized and metastatic disease, requires an interdisciplinary approach combining chemotherapy with local therapy-surgery, radiotherapy, or both. Systemic therapy remains the cornerstone of management. In the United States, the standard protocol alternates VDC (vincristine/doxorubicin/cyclophosphamide) with IE (ifosfamide/etoposide) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. After induction chemotherapy, local control is usually pursued with surgery, radiotherapy, or their combination. In patients with non-metastatic disease, 5-year survival rates range between 75% and 80%, whereas in metastatic cases survival drops to about 30% [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOver the last four decades, significant progress has been made in treating localized Ewing sarcoma with local therapy and multi-agent adjuvant chemotherapy. However, prognosis remains poor for metastatic disease, diagnosed in 20\u0026ndash;25% of patients (primarily lung metastases in 70\u0026ndash;80% and bone/bone marrow in 40\u0026ndash;45%) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Moreover, relapse occurs in 30\u0026ndash;40% of patients initially diagnosed with localized disease, rising to 60\u0026ndash;80% in those with metastases at presentation. Relapses are most often systemic (71\u0026ndash;73%), followed by combined (12\u0026ndash;18%) and local (11\u0026ndash;15%). Five-year survival after relapse is only 15\u0026ndash;25%, with local recurrences carrying a better prognosis than systemic ones [\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Controlling systemic tumor dissemination remains the main therapeutic challenge.\u003c/p\u003e"},{"header":"2. Case Presentation","content":"\u003cp\u003eWe present the case of a 45-year-old woman with a history of breast carcinoma, treated by right-sided mastectomy in 2015. In early 2023, she reported new complaints of right lumbar pain, reduced physical capacity, and recurrent episodes of painless gross hematuria.\u003c/p\u003e \u003cp\u003eInitial imaging with ultrasound followed by magnetic resonance imaging (MRI) revealed a well-demarcated lesion in the mid-portion of the right kidney, measuring 28 \u0026times; 23 \u0026times; 27 mm. The lesion protruded along the dorsal contour of the kidney and demonstrated a multicystic architecture with multiple septations, some irregular in course, with areas of nodular thickening up to 3\u0026ndash;4 mm. On T2-weighted MRI sequences, the lesion displayed mixed signal intensity, predominantly hyperintense, while the septa were markedly hypointense. The possibility of intralesional hemorrhage with hemoglobin degradation products was considered. No distant metastases were detected during staging.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn October 2023, the patient was admitted to the Clinic of Urology, University Hospital \u0026ldquo;St. Marina,\u0026rdquo; Varna, where partial resection of the renal tumor was performed.\u003c/p\u003e \u003cp\u003eHistopathology. The lesion was composed of monotonous tumor cells with scant, clear cytoplasm and round-to-oval nuclei lacking prominent nucleoli. The cells formed solid nests and Homer-Wright rosettes. Scattered foci of necrosis and numerous apoptotic bodies were observed. Mitotic activity was 5/10 HPF. PAS highlighted cytoplasmic glycogen granules.\u003c/p\u003e \u003cp\u003eImmunohistochemistry. The immunophenotype showed positivity for CD99, Cyclin D1, WT1, vimentin, S100, p53 (~\u0026thinsp;50%), and synaptophysin (~\u0026thinsp;30%); negative for CD117, CD10, inhibin, CK7, GATA3, CD34, SMA, CK AE1/AE3, HMB45, Melan-A. Ki-67\u0026thinsp;~\u0026thinsp;15%.\u003c/p\u003e \u003cp\u003eThe morphological and immunohistochemical findings were most consistent with extraskeletal Ewing sarcoma. To confirm this diagnosis, molecular genetic analysis was performed on formalin-fixed tumor tissue at an external reference laboratory (Eurofins Biomnis Lyon, France). FISH (break-apart) demonstrated EWSR1 gene rearrangement in 100% of 100 nuclei.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe differential diagnosis included other members of the \u0026ldquo;small round blue cell tumor\u0026rdquo; family, such as Wilms tumor, neuroblastoma, clear cell sarcoma of the kidney, and lymphoma. Based on the combined histological, immunohistochemical, and molecular findings, the final diagnosis of primary renal extraskeletal Ewing sarcoma was established.\u003c/p\u003e \u003cp\u003eFollowing diagnostic confirmation, the patient underwent right nephrectomy at a specialized clinic in Austria, followed by systemic chemotherapy according to the VDC/IE protocol (vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide and etoposide).\u003c/p\u003e \u003cp\u003eGiven the previous diagnosis of breast carcinoma at age 37 and the present diagnosis of a second malignant neoplasm at age 45, medical genetic counseling was undertaken to evaluate the possibility of Li-Fraumeni syndrome (germline TP53). The patient declined genetic testing.\u003c/p\u003e"},{"header":"3. Discussion","content":"\u003cp\u003eThe first documented case of renal Ewing sarcoma was reported in 1975 [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Clinical manifestations are often nonspecific, with patients most commonly presenting with pain and a palpable mass [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Due to its inherently aggressive nature, renal ES may present with advanced disease and early metastases [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe definitive diagnosis relies on histopathological examination combined with immunohistochemistry. Ewing sarcoma belongs to the group of \u0026ldquo;small round blue cell tumors.\u0026rdquo; Histologically, the differential diagnosis must first consider other neoplasms within this category, including Wilms tumor, neuroblastoma, clear cell sarcoma of the kidney, desmoplastic small round cell tumor, lymphoma, small-cell variant of osteosarcoma, and neuroendocrine tumors [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Characteristic morphological features such as Homer-Wright rosettes and diffuse, strong CD99 expression are highly suggestive, yet the gold standard for confirmation remains molecular proof of EWSR1-ETS rearrangement by FISH/RT-PCR/NGS [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In the present case, the lesion exhibited the classical morphology and immunohistochemical profile, with FISH confirmation.\u003c/p\u003e \u003cp\u003eGiven the exceptional rarity of primary renal ES, there is no established therapeutic protocol specifically tailored to this localization. Treatment strategies are therefore extrapolated from those used for osseous ES. Successful management requires a multimodal approach, combining surgery, chemotherapy, and radiotherapy [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The most commonly used chemotherapy regimen consists of VDC/IE [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Most reported cases describe radical nephrectomy as the preferred surgical intervention, although nephron-sparing procedures have occasionally been performed [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRenal ES is considered more aggressive than tumors arising in other locations, with a high propensity for local recurrence and early metastasis to lymph nodes, lungs, liver, and bone [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. This confers a poorer prognosis compared with classic osseous ES. Broader ES cohorts highlight high relapse rates and the need for vigilant surveillance [\u003cspan additionalcitationids=\"CR13 CR14 CR15 CR16\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e"},{"header":"4. Conclusions","content":"\u003cp\u003eThis case illustrates a rare extraskeletal ES with primary renal localization. The diagnostic process required integrated imaging, histopathology, immunohistochemistry, and molecular confirmation (EWSR1 rearrangement). Surgical intervention followed by VDC/IE chemotherapy provided disease control. The patient\u0026rsquo;s oncologic history raised the suspicion of Li-Fraumeni; genetic testing was declined. Awareness, interdisciplinary collaboration, and personalized strategies remain critical.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eES\u003c/strong\u003e - Ewing sarcoma\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePNET\u003c/strong\u003e - Primitive neuroectodermal tumor\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMRI\u0026nbsp;\u003c/strong\u003e- Magnetic resonance imaging\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCT\u003c/strong\u003e - Computed tomography\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIHC\u003c/strong\u003e - Immunohistochemistry\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFISH\u003c/strong\u003e - Fluorescence in situ hybridization\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePAS\u003c/strong\u003e - Periodic acid\u0026ndash;Schiff\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHPF\u003c/strong\u003e - High-power field\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVDC/IE\u003c/strong\u003e - Vincristine, doxorubicin, cyclophosphamide / Ifosfamide, etoposide\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNGS\u003c/strong\u003e - Next-generation sequencing\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization, M.B.-P. and A.P.; Investigation, M.B.-P., S.S., L.S., M.H., D.A., and A.P.; Data Curation, M.B.-P. and L.S.; Writing-Original Draft, M.B.-P.; Writing-Review \u0026amp; Editing, A.P., S.S., L.S., M.H., and D.A.; Supervision, A.P.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no external funding.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical considerations\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eand approval:\u0026nbsp;\u003cbr\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval was waived by the Ethics Committee of University Hospital \u0026ldquo;St. Marina\u0026rdquo;, Varna, as this study represents a single-patient case report with no experimental intervention beyond standard clinical care, in accordance with institutional and national ethical guidelines. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAccordance with ethical guidelines\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll procedures involving human participants were performed in accordance with institutional ethical standards and with the principles of the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent to participate in the study was obtained from the patient.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent for publication of clinical details and images was obtained from the patient.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData sharing not applicable to this article as no datasets were generated or analysed during the current study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInstitutional Review Board Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical review and approval were waived for this single-patient case report according to local regulations; no experimental intervention beyond standard care was performed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo new data were created or analyzed in this study; data sharing is not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the clinical staff involved in patient management and the collaborating pathology, urology, and medical genetics teams; we especially thank the patient for consenting to publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval:\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;The study protocol was approved by the Ethics Committee of University Hospital \u0026ldquo;St. Marina\u0026rdquo;, Varna, and all methods were performed in accordance with relevant guidelines and regulations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate:\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Written informed consent to participate was obtained from the patient.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish:\u003c/strong\u003e\u003cbr\u003e Written informed consent for publication of clinical details and images was obtained from the patient.\u003c/p\u003e"},{"header":"References","content":"\u003col start=\"1\" type=\"1\"\u003e\n \u003cli\u003e\u003cstrong\u003eLudwig JA.\u003c/strong\u003e Ewing sarcoma: historical perspectives, current state-of-the-art, and opportunities for targeted therapy in the future. \u003cem\u003eCurr Opin Oncol.\u003c/em\u003e 2008;20(4):412-418.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eOzaki T.\u003c/strong\u003e Diagnosis and treatment of Ewing sarcoma of the bone: a review article. \u003cem\u003eJ Orthop Sci.\u003c/em\u003e 2015;20(2):250-263.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eVan den Berg H, Heinen RC, van der Pal HJ, Merks JH.\u003c/strong\u003e Extra-osseous Ewing sarcoma. \u003cem\u003ePediatr Hematol Oncol.\u003c/em\u003e 2009;26:175-185. doi:10.1080/08880010902855581.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eApplebaum MA,\u003c/strong\u003e Worch J, Matthay KK, et al. Clinical features and outcomes in patients with extraskeletal Ewing sarcoma. \u003cem\u003eCancer.\u003c/em\u003e 2011;117:3027-3032. doi:10.1002/cncr.25840.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eCheung CC,\u003c/strong\u003e Kandel RA, Bell RS, Mathews RE, Ghazarian MD. Extraskeletal Ewing sarcoma in a 77-year-old woman. \u003cem\u003eArch Pathol Lab Med.\u003c/em\u003e 2001;125:1358-1360. doi:10.5858/2001-125-1358-EESIAY.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eGeens L,\u003c/strong\u003e Van Robays J, Geert V, Van der Speeten K. An unusual location of extraosseous Ewing\u0026rsquo;s sarcoma. \u003cem\u003eCase Rep Oncol.\u003c/em\u003e 2013;6:293-302. doi:10.1159/000351836.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eRiggi N, Stamenkovic I.\u003c/strong\u003e The biology of Ewing sarcoma. \u003cem\u003eCancer Lett.\u003c/em\u003e 2007;254(1):1-10.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eKovar H,\u003c/strong\u003e Aryee DN, Jug G, et al. EWS/FLI-1 antagonists induce growth inhibition of Ewing tumor cells \u003cem\u003ein vitro\u003c/em\u003e. \u003cem\u003eCell Growth Differ.\u003c/em\u003e 1996;7:429-437.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eLambert G,\u003c/strong\u003e Bertrand JR, Fattal E, et al. EWS-FLI1 antisense nanocapsules inhibit Ewing sarcoma-related tumor in mice. \u003cem\u003eBiochem Biophys Res Commun.\u003c/em\u003e 2000;279:401-406. doi:10.1006/bbrc.2000.3963.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eWidhe B, Widhe T.\u003c/strong\u003e Initial symptoms and clinical features in osteosarcoma and Ewing sarcoma. \u003cem\u003eJ Bone Joint Surg Am.\u003c/em\u003e 2000;82(5):667-674.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eGrier HE,\u003c/strong\u003e Krailo MD, Tarbell NJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing\u0026rsquo;s sarcoma and PNET of bone. \u003cem\u003eN Engl J Med.\u003c/em\u003e 2003;348(8):694-701.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eLadenstein R,\u003c/strong\u003e Potschger U, Le Deley MC, et al. Primary disseminated multifocal Ewing sarcoma: Euro-EWING 99 results. \u003cem\u003eJ Clin Oncol.\u003c/em\u003e 2010;28:3284-3291. doi:10.1200/JCO.2009.22.9864.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eLeavey PJ, Collier AB.\u003c/strong\u003e Ewing sarcoma: prognostic criteria, outcomes and future treatment. \u003cem\u003eExpert Rev Anticancer Ther.\u003c/em\u003e 2008;8(4):617-624.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eHaeusler J,\u003c/strong\u003e Ranft A, Boelling T, et al. The value of local treatment in patients with primary, disseminated, multifocal ES (PDMES). \u003cem\u003eCancer.\u003c/em\u003e 2010;116:443-450. doi:10.1002/cncr.24740.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eBarker LM,\u003c/strong\u003e Pendergrass TW, Sanders JE, Hawkins DS. Survival after recurrence of Ewing\u0026rsquo;s sarcoma family of tumors. \u003cem\u003eJ Clin Oncol.\u003c/em\u003e 2005;23:4354-4362. doi:10.1200/JCO.2005.05.105.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eRodriguez-Galindo C,\u003c/strong\u003e Billups CA, Kun LE, et al. Survival after recurrence of Ewing tumors: St. Jude experience, 1979\u0026ndash;1999. \u003cem\u003eCancer.\u003c/em\u003e 2002;94:561-569. doi:10.1002/cncr.10192.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eStahl M,\u003c/strong\u003e Ranft A, Paulussen M, et al. Risk of recurrence and survival after relapse in patients with ES. \u003cem\u003ePediatr Blood Cancer.\u003c/em\u003e 2011;57:549-553. doi:10.1002/pbc.23040.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eSeemayer TA,\u003c/strong\u003e Thelmo WL, Bolande RP, Wiglesworth FW. Peripheral neuroectodermal tumors. \u003cem\u003ePerspect Pediatr Pathol.\u003c/em\u003e 1975;2:151-172.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eEllinger J,\u003c/strong\u003e Bastian PJ, Hauser S, Biermann K, M\u0026uuml;ller SC. Primitive neuroectodermal tumor: rare, highly aggressive differential diagnosis in urologic malignancies. \u003cem\u003eUrology.\u003c/em\u003e 2006;68:257-262. doi:10.1016/j.urology.2006.02.037.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eTarek N,\u003c/strong\u003e Said R, Andersen CR, et al. Primary renal ES/PNET: MD Anderson experience. \u003cem\u003eCancers (Basel).\u003c/em\u003e 2020;12:2927. doi:10.3390/cancers12102927.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eAlmeida MF,\u003c/strong\u003e Patnana M, Korivi BR, Kalhor N, Marcal L. Ewing sarcoma of the kidney: a rare entity. \u003cem\u003eCase Rep Radiol.\u003c/em\u003e 2014;2014:283902. doi:10.1155/2014/283902.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eDoroudinia A,\u003c/strong\u003e Ahmadi S, Mehrian P, Pourabdollah M. Primary Ewing sarcoma of the kidney. \u003cem\u003eBMJ Case Rep.\u003c/em\u003e 2019;12(1):bcr-2018-227198. doi:10.1136/bcr-2018-227198.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eYoshida A.\u003c/strong\u003e Ewing and Ewing-like sarcomas: a morphological guide through genetically-defined entities. \u003cem\u003ePathology International.\u003c/em\u003e doi:10.1111/pin.13293.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eSuzuki I,\u003c/strong\u003e Kubota M, Murata S, et al. A case of ES family tumor of the kidney treated with robotic-assisted partial nephrectomy. \u003cem\u003eUrol Case Rep.\u003c/em\u003e 2019;25:100900. doi:10.1016/j.eucr.2019.100900.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eHakky TS,\u003c/strong\u003e Gonzalvo AA, Lockhart JL, Rodriguez AR. Primary renal ES: symptomatic presentation and literature review. \u003cem\u003eTher Adv Urol.\u003c/em\u003e 2013;5:153-159. doi:10.1177/1756287212471095.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eParham DM,\u003c/strong\u003e Roloson GJ, Feely M, Green DM, Bridge JA, Beckwith JB. Primary malignant neuroepithelial tumors of the kidney: analysis of 146 cases. \u003cem\u003eAm J Surg Pathol.\u003c/em\u003e 2001;25:133-146. doi:10.1097/00000478-200102000-00001.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Ewing sarcoma, primary renal, extraskeletal tumor, EWSR1 rearrangement, FISH analysis, nephrectomy, VDC/IE, Li-Fraumeni syndrome, case report","lastPublishedDoi":"10.21203/rs.3.rs-8309965/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8309965/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Ewing sarcoma is a rare but aggressive malignant tumor that primarily affects adolescents and young adults. Although it typically arises in bone, in rare cases it may originate in parenchymal organs such as the kidney.\u003cbr\u003e\n \u003cstrong\u003eCase Presentation:\u003c/strong\u003e We present a 45-year-old woman with a history of breast carcinoma and a right renal mass. Imaging revealed a multicystic lesion with septations and nodular thickening. Histology and immunohistochemistry were consistent with extraskeletal Ewing sarcoma; FISH confirmed the characteristic rearrangement (t(11;22)(q24;q12)/EWSR1-ETS). The patient underwent nephrectomy followed by VDC/IE chemotherapy. Given her oncologic history and age, Li-Fraumeni syndrome was considered.\u003cbr\u003e\n \u003cstrong\u003eConclusions:\u003c/strong\u003e This case highlights a rare primary renal localization of Ewing sarcoma and underscores the value of a multidisciplinary approach with molecular confirmation to secure diagnosis and guide therapy.\u003c/p\u003e","manuscriptTitle":"Ewing Sarcoma Beyond the Bone A Rare Primary renal presentation care report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-05 06:16:58","doi":"10.21203/rs.3.rs-8309965/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c40c4a7a-2056-4bee-8d14-09cb94a08203","owner":[],"postedDate":"January 5th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-14T04:55:14+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-05 06:16:58","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8309965","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8309965","identity":"rs-8309965","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}