Pleural Ewing's Sarcoma in Young Women: A Report of Two Cases and Review of the Literature

Pleural Ewing's Sarcoma in Young Women: A Report of Two Cases and Review of the Literature | 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 Pleural Ewing's Sarcoma in Young Women: A Report of Two Cases and Review of the Literature Mehdi Alem, Sara Nejjari, Assiya Benamar, Mounir Belcadi Abbassi, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9067566/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's sarcoma (ES) arising from the pleura is an exceedingly rare entity, accounting for fewer than 2% of all ES cases. Its rarity and non-specific clinical presentation frequently result in diagnostic delays and therapeutic challenges. Case Presentations: We report two young female patients with histologically confirmed pleural ES managed at our institution. The first, a 25-year-old woman, presented with a large locally advanced left pleural ES and received six cycles of VIDE (vincristine, ifosfamide, doxorubicin, etoposide) neoadjuvant chemotherapy, achieving an initial response followed by metastatic progression requiring second-line gemcitabine-docetaxel. The second, an 18-year-old woman, presented with a locally advanced right latero-thoracic soft-tissue ES with pleural involvement and was treated with three cycles of VDC-IE (vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide and etoposide), achieving a 73% partial response; surgical resection was declined and she was referred for consolidative radiotherapy. Conclusion Pleural ES is an aggressive malignancy requiring multidisciplinary management. Immunohistochemical confirmation (CD99 positivity) and cytogenetic analysis are essential for diagnosis. Multimodal treatment including chemotherapy, surgery, and radiotherapy remains the cornerstone of management. Our cases highlight the rarity of this tumor, the importance of early diagnosis, and the significant therapeutic challenges posed by locally advanced disease. Sarcoma Ewing Pleural Neoplasms Neuroectodermal Tumors Primitive Peripheral Antineoplastic Combined Chemotherapy Protocols Thoracic Neoplasms Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Highlights • Pleural Ewing's sarcoma accounts for fewer than 2% of all ES cases. • CD99 immunopositivity and EWSR1 rearrangement are essential for diagnosis. • Multimodal therapy (chemotherapy, surgery, radiotherapy) is the standard of care. • Locally advanced disease poses major therapeutic challenges in resource-limited settings. • Social determinants of health significantly impact oncological outcomes. 1. Introduction Ewing's sarcoma (ES) is the second most common primary malignant bone tumor in children and young adults, following osteosarcoma [ 1 ]. It belongs to the Ewing's sarcoma family of tumors (ESFT), which encompasses a spectrum of small round-cell tumors including primitive neuroectodermal tumors (PNET) and Askin tumors of the chest wall, all unified by specific chromosomal translocations predominantly involving the EWS gene on chromosome 22 [ 2 ]. Although ES most commonly arises in the diaphysis of long bones, primary extraskeletal ES involving soft tissues or serosal surfaces has been increasingly recognized. Pleural ES is an exceptionally rare subtype, with fewer than 100 cases reported in the world literature to date [ 3 ]. The pleural location presents distinctive diagnostic and therapeutic challenges: the tumor must be distinguished from other aggressive pleural malignancies such as malignant mesothelioma, synovial sarcoma, and metastatic carcinoma, and the extensive local involvement frequently precludes complete surgical resection [ 4 ]. The prognosis of extraskeletal ES remains poor, particularly in cases with locally advanced disease or metastatic dissemination. Multimodal therapy—incorporating intensive systemic chemotherapy and local control through surgery and/or radiotherapy—represents the standard of care; however, the optimal treatment strategy for pleural ES has not been established given the paucity of cases [ 5 ]. Herein, we report two young female patients with histologically confirmed pleural ES managed at our institution, with a review of the existing literature regarding this rare entity. All procedures were performed in compliance with the ethical standards of the Declaration of Helsinki, and written informed consent was obtained from both patients. 2. Case Report 1 2.1. Clinical Presentation A 25-year-old woman with no significant past medical or surgical history presented with a two-month history of progressive dry cough, exertional dyspnea, and left-sided chest pain associated with weight loss. Chest radiography performed by the referring physician revealed a large left pleural effusion. She was hospitalized locally where three non-diagnostic pleural taps were performed before being referred to our center for further evaluation. 2.2. Diagnostic Work-up On physical examination, the patient had an Eastern Cooperative Oncology Group (ECOG) performance status of 1. Computed tomography (CT) of the chest, abdomen, and pelvis demonstrated a massive left pleural process with an associated loculated pleural effusion (Fig. 1 ). A CT-guided pleural biopsy confirmed the diagnosis of PNET/Ewing's sarcoma of pleural location. Histological sections showed cells with scanty cytoplasm, hyperchromatic nuclei and rosette formation (Fig. 2 ). Immunohistochemistry (IHC) demonstrated strong and diffuse membranous CD99 positivity (Fig. 3 ). Fluorescence in situ hybridization (FISH) analysis for EWSR1 gene rearrangement [t(11;22)] was requested to confirm the diagnosis. A bone marrow trephine biopsy showed no medullary infiltration, and bone scintigraphy revealed no skeletal secondary lesions. 2.3. Treatment and Clinical Course After multidisciplinary team (MDT) discussion, the patient commenced neoadjuvant chemotherapy with the VIDE protocol (vincristine 1.5 mg/m², ifosfamide 3 g/m²/day for 3 days, doxorubicin 20 mg/m²/day for 3 days, etoposide 150 mg/m²/day for 3 days), administered every 21 days. Following three cycles, re-evaluation demonstrated a significant clinical and radiological response, and the decision was made to complete a total of six cycles before reassessing surgical feasibility. After completing six cycles of VIDE, restaging CT showed apparent stability of the left pleural tumor process but with the new appearance of left pulmonary secondary nodules—consistent with frank metastatic progression. Second-line chemotherapy with gemcitabine (900 mg/m² on days 1 and 8) and docetaxel (75 mg/m² on day 8) every 21 days was initiated. The patient experienced significant haematological toxicity including grade 3 thrombocytopenia necessitating dose reductions, anaemia requiring red blood cell transfusion, and a febrile pancytopenia episode complicated by Escherichia coli bacteraemia, which was managed with broad-spectrum intravenous antibiotics with full recovery. Given the metastatic progression and cumulative toxicity, palliative care was ultimately recommended. The patient's condition deteriorated progressively and she died from disease progression. 3. Case Report 2 3.1. Clinical Presentation An 18-year-old woman with no relevant personal or family medical history presented with a 12-month history of a rapidly enlarging right sub-mammary paracostal soft-tissue swelling. Initial plain radiography described a right basal pleural homogeneous opacity (Fig. 4 ) and recommended CT or MRI for further characterization. 3.2. Diagnostic Work-up CT of the chest, abdomen, and pelvis revealed a large right-sided pleural mass (Fig. 5 ). A soft-tissue biopsy performed at the referring institution showed an undifferentiated malignant small round-cell tumor consistent with Ewing's sarcoma (Fig. 6 ). IHC confirmed strong CD99 membrane positivity (Fig. 7 ). A bone scan suggested secondary osseous involvement of the right eighth rib by contiguity, with no evidence of further distant bone metastases. Thoracocentesis drained a straw-colored exudative pleural fluid. Echocardiography confirmed preserved biventricular function with a left ventricular ejection fraction of 65%. 3.3. Treatment and Clinical Course Following MDT discussion, chemotherapy was initiated with the alternating VDC-IE protocol: vincristine (2 mg flat), doxorubicin (75 mg/m²), and cyclophosphamide (1,200 mg/m²) alternating every three weeks with ifosfamide (1,800 mg/m²/day for 5 days) and etoposide (100 mg/m²/day for 5 days), with granulocyte colony-stimulating factor (G-CSF) support. Three cycles were completed with good clinical tolerance (ECOG PS 1), and doxorubicin was replaced by dactinomycin after the cumulative dose of 375 mg/m² was reached. Restaging CT demonstrated a marked partial response with significant regression of the primary mass (30 × 38 × 49 mm versus 115 × 111 × 89 mm at baseline—a reduction of approximately 73% in longest diameter), together with partial regression of the right pleural effusion. Surgical resection was declined given the very high surgical morbidity and limited oncological benefit, and the patient was referred for consolidative radiotherapy. The patient is currently under regular follow-up. 4. Discussion Ewing's sarcoma of the pleura is a rare and aggressive malignancy that poses substantial diagnostic and therapeutic challenges. Our two cases align with the established literature regarding the typical patient profile: young women in their second or third decade of life presenting with large, locally advanced thoracic masses [ 6 ]. The rarity of this condition—estimated at fewer than 2% of all ES cases—means that most published data derive from case reports and small series, and no prospective randomized trial has specifically addressed the management of pleural ES [ 3 ]. The clinical presentation of pleural ES is non-specific, with dyspnea, chest pain, and weight loss being the most frequently reported symptoms. Pleural effusion, often of large volume, is a characteristic radiological finding [ 7 ]. CT demonstrates a large, heterogeneous, extra-pleural mass with variable osseous involvement; periosteal sunburst reaction may be identified when rib involvement is present, as in our second patient [ 8 ]. The definitive diagnosis of pleural ES rests on histopathological and immunohistochemical analysis. Morphologically, ES is characterized by sheets of small, monotonous round cells with scant cytoplasm, fine chromatin, and inconspicuous nucleoli, often with foci of necrosis [ 9 ]. CD99 strong membranous positivity is the most sensitive immunohistochemical marker, present in more than 95% of ES cases; it was demonstrated in both our patients [ 10 ]. Molecular confirmation of EWSR1-ETS gene rearrangement—most frequently t(11;22)(q24;q12) producing the EWS-FLI1 fusion transcript—is the gold standard for diagnosis [ 11 ]. Given the morphological overlap with other small round-cell tumors of the chest, a comprehensive immunohistochemical panel is mandatory [ 12 ]. The standard chemotherapy regimens for ES—VIDE/VAIA in the European tradition and VDC-IE in the North American approach—were both employed in our patients, reflecting current international guidelines [ 13 , 14 ]. An objective clinical and radiological response was documented in both cases, consistent with published series reporting response rates of 60–80% to first-line chemotherapy in ES [ 15 ]. Our first patient ultimately developed frank metastatic progression after six VIDE cycles, requiring second-line gemcitabine-docetaxel; this combination has demonstrated modest activity in relapsed/refractory ES, with overall response rates of approximately 17–37% in small series [ 16 ]. Local control in ES is achieved through surgery, radiotherapy, or a combination of both. Complete surgical resection with adequate margins is associated with improved event-free and overall survival [ 17 ]. However, the pleural location frequently renders complete excision technically impossible or associated with unacceptable morbidity. Definitive radiotherapy to doses of 45–56 Gy represents the standard alternative for unresectable ES, with local control rates of approximately 60–70% [ 18 ]. The delay in initiating radiotherapy in our second patient due to administrative and social barriers underscores the important role of social determinants of health in oncological outcomes in resource-limited settings. Haematological toxicity—including febrile neutropenia, anaemia, and thrombocytopenia—represents the most clinically significant treatment complication, as documented in our first patient, who required transfusional support, dose reductions, and antibiotic therapy for bacteraemic neutropenic fever. These findings emphasize the importance of close haematological monitoring, prophylactic G-CSF, and prompt management of infectious complications during intensive chemotherapy [ 19 ]. The prognosis of localized ES treated with multimodal therapy is relatively favorable, with 5-year overall survival rates of 60–70%; however, metastatic or unresectable disease carries a substantially worse prognosis, with 5-year survival rates below 30% [ 20 ]. The specific prognostic impact of pleural location is difficult to assess given the small number of reported cases. 5. Conclusions Pleural Ewing's sarcoma is an exceptionally rare and aggressive malignancy that should be considered in the differential diagnosis of young patients presenting with large thoracic masses and pleural effusion. Diagnosis requires a combination of histopathological, immunohistochemical (CD99), and molecular analyses. Multidisciplinary management incorporating intensive chemotherapy and local control—through surgery when feasible, or radiotherapy for unresectable disease—remains the cornerstone of treatment. Our two cases illustrate both the diagnostic challenges and the therapeutic complexity of this entity, and highlight the need for international collaborative studies to optimize treatment strategies in this rare tumor. Declarations Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Declaration of Generative AI and AI-assisted Technologies in the Manuscript Preparation Process During the preparation of this work the authors used Claude (Anthropic) in order to assist with language editing and formatting. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the published article. CRediT Author Contribution Statement Mehdi Alem: Conceptualization, Data curation, Writing – original draft, Writing – review and editing. Sara Nejjari: Data curation, Writing – review and editing. Assiya Benamar: Resources, Writing – review and editing. Mounir Belcadi Abbassi, Maryam Msakem, Diango Keita, Lamiae Amaadour, Karima Oualla, Zineb Benbrahim: Writing – review and editing. Samia Arifi, Nawfel Mellas: Supervision, Writing – review and editing. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Ethical Approval and Consent All procedures were performed in compliance with relevant laws and institutional guidelines and in accordance with the ethical standards of the Declaration of Helsinki. Written informed consent was obtained from both patients (or their legal guardians) for the publication of their anonymized clinical data and images. Data Availability No data were used for the research described in this article. 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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-9067566","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":603333422,"identity":"3f48bd6c-4648-4c10-be7e-ab0dbdb02574","order_by":0,"name":"Mehdi 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revealing a large heterogeneous soft-tissue mass with gross left pleural effusion, collapse of the left lung, cortical destruction and expansion of the adjacent 7th rib.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9067566/v1/6097d118f085d977a1ec601f.png"},{"id":104342468,"identity":"ab5c5e9b-9673-405f-939e-a8a501abe5f2","added_by":"auto","created_at":"2026-03-10 17:03:30","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":524664,"visible":true,"origin":"","legend":"\u003cp\u003eMicrophotograph of the biopsy specimen showing tumour cells with scanty cytoplasm and rosette formation (Haematoxylin and Eosin, ×125 digital 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basal pleural opacity (black arrow).\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-9067566/v1/96119a6def9c66a2ca52dfd7.png"},{"id":104405820,"identity":"31c74e34-ff4a-450d-885f-0cf2fa807e19","added_by":"auto","created_at":"2026-03-11 12:23:54","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":379560,"visible":true,"origin":"","legend":"\u003cp\u003e(A) Parenchymal CT section showing a right-sided pleural mass (black arrow). (B) Mediastinal CT section revealing the pleural mass in the right chest (red arrow). (C) Coronal chest CT scan revealing the right-sided pleural mass (blue arrow) with heterogeneous enhancement after contrast injection.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-9067566/v1/b8c8a865e9c4b8a56af606d9.png"},{"id":104342467,"identity":"55f5d667-9b6f-4030-91cb-806b7dfc9d92","added_by":"auto","created_at":"2026-03-10 17:03:30","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":676141,"visible":true,"origin":"","legend":"\u003cp\u003eTrucut biopsy from the mass showing uniform round cells with hyperchromatic nuclei, inconspicuous nucleoli and scanty cytoplasm with areas of necrosis, compatible with Ewing's sarcoma/PNET.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-9067566/v1/607063a7bafc3eaab627b61c.png"},{"id":104342463,"identity":"4c7e4b11-46d6-4ded-a6ab-b7f5c47dcbc6","added_by":"auto","created_at":"2026-03-10 17:03:30","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":809317,"visible":true,"origin":"","legend":"\u003cp\u003eImmunohistochemistry showing strong membranous positivity for CD99.\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-9067566/v1/78c7a523ac657010394c4a19.png"},{"id":105562575,"identity":"cb60d23e-34b2-4c25-9130-5ffbff29f12d","added_by":"auto","created_at":"2026-03-27 12:43:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5552350,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9067566/v1/ffc4d11c-5e78-4919-9aba-5956a649c51d.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Pleural Ewing's Sarcoma in Young Women: A Report of Two Cases and Review of the Literature","fulltext":[{"header":"Highlights","content":"\u003cp\u003e\u0026bull; Pleural Ewing\u0026apos;s sarcoma accounts for fewer than 2% of all ES cases.\u003c/p\u003e\n\u003cp\u003e\u0026bull; CD99 immunopositivity and EWSR1 rearrangement are essential for diagnosis.\u003c/p\u003e\n\u003cp\u003e\u0026bull; Multimodal therapy (chemotherapy, surgery, radiotherapy) is the standard of care.\u003c/p\u003e\n\u003cp\u003e\u0026bull; Locally advanced disease poses major therapeutic challenges in resource-limited settings.\u003c/p\u003e\n\u003cp\u003e\u0026bull; Social determinants of health significantly impact oncological outcomes.\u003c/p\u003e"},{"header":"1. Introduction","content":"\u003cp\u003eEwing's sarcoma (ES) is the second most common primary malignant bone tumor in children and young adults, following osteosarcoma [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. It belongs to the Ewing's sarcoma family of tumors (ESFT), which encompasses a spectrum of small round-cell tumors including primitive neuroectodermal tumors (PNET) and Askin tumors of the chest wall, all unified by specific chromosomal translocations predominantly involving the EWS gene on chromosome 22 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough ES most commonly arises in the diaphysis of long bones, primary extraskeletal ES involving soft tissues or serosal surfaces has been increasingly recognized. Pleural ES is an exceptionally rare subtype, with fewer than 100 cases reported in the world literature to date [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The pleural location presents distinctive diagnostic and therapeutic challenges: the tumor must be distinguished from other aggressive pleural malignancies such as malignant mesothelioma, synovial sarcoma, and metastatic carcinoma, and the extensive local involvement frequently precludes complete surgical resection [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe prognosis of extraskeletal ES remains poor, particularly in cases with locally advanced disease or metastatic dissemination. Multimodal therapy\u0026mdash;incorporating intensive systemic chemotherapy and local control through surgery and/or radiotherapy\u0026mdash;represents the standard of care; however, the optimal treatment strategy for pleural ES has not been established given the paucity of cases [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHerein, we report two young female patients with histologically confirmed pleural ES managed at our institution, with a review of the existing literature regarding this rare entity. All procedures were performed in compliance with the ethical standards of the Declaration of Helsinki, and written informed consent was obtained from both patients.\u003c/p\u003e"},{"header":"2. Case Report 1","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Clinical Presentation\u003c/h2\u003e \u003cp\u003eA 25-year-old woman with no significant past medical or surgical history presented with a two-month history of progressive dry cough, exertional dyspnea, and left-sided chest pain associated with weight loss. Chest radiography performed by the referring physician revealed a large left pleural effusion. She was hospitalized locally where three non-diagnostic pleural taps were performed before being referred to our center for further evaluation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Diagnostic Work-up\u003c/h2\u003e \u003cp\u003eOn physical examination, the patient had an Eastern Cooperative Oncology Group (ECOG) performance status of 1. Computed tomography (CT) of the chest, abdomen, and pelvis demonstrated a massive left pleural process with an associated loculated pleural effusion (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e1\u003c/span\u003e). A CT-guided pleural biopsy confirmed the diagnosis of PNET/Ewing's sarcoma of pleural location. Histological sections showed cells with scanty cytoplasm, hyperchromatic nuclei and rosette formation (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Immunohistochemistry (IHC) demonstrated strong and diffuse membranous CD99 positivity (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Fluorescence in situ hybridization (FISH) analysis for EWSR1 gene rearrangement [t(11;22)] was requested to confirm the diagnosis. A bone marrow trephine biopsy showed no medullary infiltration, and bone scintigraphy revealed no skeletal secondary lesions.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Treatment and Clinical Course\u003c/h2\u003e \u003cp\u003eAfter multidisciplinary team (MDT) discussion, the patient commenced neoadjuvant chemotherapy with the VIDE protocol (vincristine 1.5 mg/m\u0026sup2;, ifosfamide 3 g/m\u0026sup2;/day for 3 days, doxorubicin 20 mg/m\u0026sup2;/day for 3 days, etoposide 150 mg/m\u0026sup2;/day for 3 days), administered every 21 days. Following three cycles, re-evaluation demonstrated a significant clinical and radiological response, and the decision was made to complete a total of six cycles before reassessing surgical feasibility.\u003c/p\u003e \u003cp\u003eAfter completing six cycles of VIDE, restaging CT showed apparent stability of the left pleural tumor process but with the new appearance of left pulmonary secondary nodules\u0026mdash;consistent with frank metastatic progression. Second-line chemotherapy with gemcitabine (900 mg/m\u0026sup2; on days 1 and 8) and docetaxel (75 mg/m\u0026sup2; on day 8) every 21 days was initiated. The patient experienced significant haematological toxicity including grade 3 thrombocytopenia necessitating dose reductions, anaemia requiring red blood cell transfusion, and a febrile pancytopenia episode complicated by Escherichia coli bacteraemia, which was managed with broad-spectrum intravenous antibiotics with full recovery. Given the metastatic progression and cumulative toxicity, palliative care was ultimately recommended. The patient's condition deteriorated progressively and she died from disease progression.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Case Report 2","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e3.1. Clinical Presentation\u003c/h2\u003e \u003cp\u003eAn 18-year-old woman with no relevant personal or family medical history presented with a 12-month history of a rapidly enlarging right sub-mammary paracostal soft-tissue swelling. Initial plain radiography described a right basal pleural homogeneous opacity (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e4\u003c/span\u003e) and recommended CT or MRI for further characterization.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.2. Diagnostic Work-up\u003c/h2\u003e \u003cp\u003eCT of the chest, abdomen, and pelvis revealed a large right-sided pleural mass (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e5\u003c/span\u003e). A soft-tissue biopsy performed at the referring institution showed an undifferentiated malignant small round-cell tumor consistent with Ewing's sarcoma (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e6\u003c/span\u003e). IHC confirmed strong CD99 membrane positivity (Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e7\u003c/span\u003e). A bone scan suggested secondary osseous involvement of the right eighth rib by contiguity, with no evidence of further distant bone metastases. Thoracocentesis drained a straw-colored exudative pleural fluid. Echocardiography confirmed preserved biventricular function with a left ventricular ejection fraction of 65%.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.3. Treatment and Clinical Course\u003c/h2\u003e \u003cp\u003eFollowing MDT discussion, chemotherapy was initiated with the alternating VDC-IE protocol: vincristine (2 mg flat), doxorubicin (75 mg/m\u0026sup2;), and cyclophosphamide (1,200 mg/m\u0026sup2;) alternating every three weeks with ifosfamide (1,800 mg/m\u0026sup2;/day for 5 days) and etoposide (100 mg/m\u0026sup2;/day for 5 days), with granulocyte colony-stimulating factor (G-CSF) support. Three cycles were completed with good clinical tolerance (ECOG PS 1), and doxorubicin was replaced by dactinomycin after the cumulative dose of 375 mg/m\u0026sup2; was reached.\u003c/p\u003e \u003cp\u003eRestaging CT demonstrated a marked partial response with significant regression of the primary mass (30 \u0026times; 38 \u0026times; 49 mm versus 115 \u0026times; 111 \u0026times; 89 mm at baseline\u0026mdash;a reduction of approximately 73% in longest diameter), together with partial regression of the right pleural effusion. Surgical resection was declined given the very high surgical morbidity and limited oncological benefit, and the patient was referred for consolidative radiotherapy. The patient is currently under regular follow-up.\u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eEwing's sarcoma of the pleura is a rare and aggressive malignancy that poses substantial diagnostic and therapeutic challenges. Our two cases align with the established literature regarding the typical patient profile: young women in their second or third decade of life presenting with large, locally advanced thoracic masses [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The rarity of this condition\u0026mdash;estimated at fewer than 2% of all ES cases\u0026mdash;means that most published data derive from case reports and small series, and no prospective randomized trial has specifically addressed the management of pleural ES [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe clinical presentation of pleural ES is non-specific, with dyspnea, chest pain, and weight loss being the most frequently reported symptoms. Pleural effusion, often of large volume, is a characteristic radiological finding [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. CT demonstrates a large, heterogeneous, extra-pleural mass with variable osseous involvement; periosteal sunburst reaction may be identified when rib involvement is present, as in our second patient [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe definitive diagnosis of pleural ES rests on histopathological and immunohistochemical analysis. Morphologically, ES is characterized by sheets of small, monotonous round cells with scant cytoplasm, fine chromatin, and inconspicuous nucleoli, often with foci of necrosis [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. CD99 strong membranous positivity is the most sensitive immunohistochemical marker, present in more than 95% of ES cases; it was demonstrated in both our patients [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Molecular confirmation of EWSR1-ETS gene rearrangement\u0026mdash;most frequently t(11;22)(q24;q12) producing the EWS-FLI1 fusion transcript\u0026mdash;is the gold standard for diagnosis [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Given the morphological overlap with other small round-cell tumors of the chest, a comprehensive immunohistochemical panel is mandatory [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe standard chemotherapy regimens for ES\u0026mdash;VIDE/VAIA in the European tradition and VDC-IE in the North American approach\u0026mdash;were both employed in our patients, reflecting current international guidelines [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. An objective clinical and radiological response was documented in both cases, consistent with published series reporting response rates of 60\u0026ndash;80% to first-line chemotherapy in ES [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Our first patient ultimately developed frank metastatic progression after six VIDE cycles, requiring second-line gemcitabine-docetaxel; this combination has demonstrated modest activity in relapsed/refractory ES, with overall response rates of approximately 17\u0026ndash;37% in small series [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eLocal control in ES is achieved through surgery, radiotherapy, or a combination of both. Complete surgical resection with adequate margins is associated with improved event-free and overall survival [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. However, the pleural location frequently renders complete excision technically impossible or associated with unacceptable morbidity. Definitive radiotherapy to doses of 45\u0026ndash;56 Gy represents the standard alternative for unresectable ES, with local control rates of approximately 60\u0026ndash;70% [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The delay in initiating radiotherapy in our second patient due to administrative and social barriers underscores the important role of social determinants of health in oncological outcomes in resource-limited settings.\u003c/p\u003e \u003cp\u003eHaematological toxicity\u0026mdash;including febrile neutropenia, anaemia, and thrombocytopenia\u0026mdash;represents the most clinically significant treatment complication, as documented in our first patient, who required transfusional support, dose reductions, and antibiotic therapy for bacteraemic neutropenic fever. These findings emphasize the importance of close haematological monitoring, prophylactic G-CSF, and prompt management of infectious complications during intensive chemotherapy [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe prognosis of localized ES treated with multimodal therapy is relatively favorable, with 5-year overall survival rates of 60\u0026ndash;70%; however, metastatic or unresectable disease carries a substantially worse prognosis, with 5-year survival rates below 30% [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The specific prognostic impact of pleural location is difficult to assess given the small number of reported cases.\u003c/p\u003e"},{"header":"5. Conclusions","content":"\u003cp\u003ePleural Ewing's sarcoma is an exceptionally rare and aggressive malignancy that should be considered in the differential diagnosis of young patients presenting with large thoracic masses and pleural effusion. Diagnosis requires a combination of histopathological, immunohistochemical (CD99), and molecular analyses. Multidisciplinary management incorporating intensive chemotherapy and local control\u0026mdash;through surgery when feasible, or radiotherapy for unresectable disease\u0026mdash;remains the cornerstone of treatment. Our two cases illustrate both the diagnostic challenges and the therapeutic complexity of this entity, and highlight the need for international collaborative studies to optimize treatment strategies in this rare tumor.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of Generative AI and AI-assisted Technologies in the Manuscript Preparation Process\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring the preparation of this work the authors used Claude (Anthropic) in order to assist with language editing and formatting. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the published article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCRediT Author Contribution Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMehdi Alem:\u0026nbsp;\u003c/strong\u003eConceptualization, Data curation, Writing – original draft, Writing – review and editing. \u003cstrong\u003eSara Nejjari:\u0026nbsp;\u003c/strong\u003eData curation, Writing – review and editing. \u003cstrong\u003eAssiya Benamar:\u0026nbsp;\u003c/strong\u003eResources, Writing – review and editing. \u003cstrong\u003eMounir Belcadi Abbassi, Maryam Msakem, Diango Keita, Lamiae Amaadour, Karima Oualla, Zineb Benbrahim:\u0026nbsp;\u003c/strong\u003eWriting – review and editing. \u003cstrong\u003eSamia Arifi, Nawfel Mellas:\u0026nbsp;\u003c/strong\u003eSupervision, Writing – review and editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of Competing Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval and Consent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll procedures were performed in compliance with relevant laws and institutional guidelines and in accordance with the ethical standards of the Declaration of Helsinki. Written informed consent was obtained from both patients (or their legal guardians) for the publication of their anonymized clinical data and images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo data were used for the research described in this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank the medical and nursing staff of the Medical Oncology and Radiotherapy Departments at Hassan II University Hospital, Fez, for their dedicated care of these patients.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eT.G.P. Gr\u0026uuml;newald, F. Cidre-Aranaz, D. Surdez, et al., Ewing sarcoma, Nat. Rev. Dis. Primers 4 (2018) 5. https://doi.org/10.1038/s41572-018-0003-x\u003c/li\u003e\n\u003cli\u003eO. Delattre, J. Zucman, B. 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Oncol. 26 (2008) 4385\u0026ndash;4393. https://doi.org/10.1200/JCO.2008.16.5720\u003c/li\u003e\n\u003cli\u003eM. Stahl, A. Ranft, M. Paulussen, et al., Risk of recurrence and survival after relapse in patients with Ewing sarcoma, Pediatr. Blood Cancer 57 (2011) 549\u0026ndash;553. https://doi.org/10.1002/pbc.23040\u003c/li\u003e\n\u003cli\u003eG. Bacci, S. Ferrari, A. Longhi, et al., Role of surgery in local treatment of Ewing\u0026apos;s sarcoma of the extremities in patients undergoing adjuvant and neoadjuvant chemotherapy, Oncol. Rep. 11 (2004) 111\u0026ndash;120. https://doi.org/10.3892/or.11.1.111\u003c/li\u003e\n\u003cli\u003eS. Laskar, G. Bahl, M.A. Muckaden, et al., Definitive radiation therapy for Ewing sarcoma family of tumors, Cancer 113 (2008) 2503\u0026ndash;2510. https://doi.org/10.1002/cncr.23866\u003c/li\u003e\n\u003cli\u003eS. Cesaro, T. Toffolutti, C. Messina, et al., Safety and efficacy of caspofungin and liposomal amphotericin B, followed by voriconazole in young patients affected by refractory invasive mycosis, Eur. J. Haematol. 73 (2004) 50\u0026ndash;55. https://doi.org/10.1111/j.1600-0609.2004.00255.x\u003c/li\u003e\n\u003cli\u003eR. Ladenstein, U. P\u0026ouml;tschger, M.C. Le Deley, et al., Primary disseminated multifocal Ewing sarcoma: results of the Euro-EWING 99 trial, J. Clin. Oncol. 28 (2010) 3284\u0026ndash;3291. https://doi.org/10.1200/JCO.2009.22.9864\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"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":"Sarcoma, Ewing, Pleural Neoplasms, Neuroectodermal Tumors, Primitive, Peripheral, Antineoplastic Combined Chemotherapy Protocols, Thoracic Neoplasms","lastPublishedDoi":"10.21203/rs.3.rs-9067566/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9067566/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eEwing's sarcoma (ES) arising from the pleura is an exceedingly rare entity, accounting for fewer than 2% of all ES cases. Its rarity and non-specific clinical presentation frequently result in diagnostic delays and therapeutic challenges.\u003c/p\u003e\u003ch2\u003eCase Presentations:\u003c/h2\u003e \u003cp\u003eWe report two young female patients with histologically confirmed pleural ES managed at our institution. The first, a 25-year-old woman, presented with a large locally advanced left pleural ES and received six cycles of VIDE (vincristine, ifosfamide, doxorubicin, etoposide) neoadjuvant chemotherapy, achieving an initial response followed by metastatic progression requiring second-line gemcitabine-docetaxel. The second, an 18-year-old woman, presented with a locally advanced right latero-thoracic soft-tissue ES with pleural involvement and was treated with three cycles of VDC-IE (vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide and etoposide), achieving a 73% partial response; surgical resection was declined and she was referred for consolidative radiotherapy.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003ePleural ES is an aggressive malignancy requiring multidisciplinary management. Immunohistochemical confirmation (CD99 positivity) and cytogenetic analysis are essential for diagnosis. Multimodal treatment including chemotherapy, surgery, and radiotherapy remains the cornerstone of management. Our cases highlight the rarity of this tumor, the importance of early diagnosis, and the significant therapeutic challenges posed by locally advanced disease.\u003c/p\u003e","manuscriptTitle":"Pleural Ewing's Sarcoma in Young Women: A Report of Two Cases and Review of the Literature","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-10 17:03:25","doi":"10.21203/rs.3.rs-9067566/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":"c3d07cde-aec4-4b4f-9667-214efdc57cdb","owner":[],"postedDate":"March 10th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-10T17:03:27+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-10 17:03:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9067566","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9067566","identity":"rs-9067566","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}