Metastatic Giant Cell Bladder Variant of Urothelial Carcinoma: Description of a rare Case Report successfully treated by a 3 rd line chemotherapy with weekly paclitaxel

Metastatic Giant Cell Bladder Variant of Urothelial Carcinoma: Description of a rare Case Report successfully treated by a 3 rd line chemotherapy with weekly paclitaxel | 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 Metastatic Giant Cell Bladder Variant of Urothelial Carcinoma: Description of a rare Case Report successfully treated by a 3 rd line chemotherapy with weekly paclitaxel Gaia Rachele Oliva, Davide Leo, Marco Campitiello, Francesca Plastino, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7162421/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 8 You are reading this latest preprint version Abstract Background The giant cell variant of urothelial carcinoma (GCVUC) is an exceptionally rare and highly aggressive histologic subtype of bladder cancer, histologically characterized by pleomorphic multinucleated giant cells. Due to the lack of clinical data, its clinical behavior and optimal management remain poorly defined. Case presentation We report the case of a Caucasian, 52-year-old, no-smoker woman presenting with pelvic pain and hematuria and diagnosed with a locally advanced GCVUC. The patient initially received a neoadjuvant dose-dense MVAC chemotherapy followed by anterior pelvic exenteration with a pathological partial response. After metastatic recurrence, she underwent two lines of systemic therapy, including cisplatin/gemcitabine chemotherapy and immunotherapy. Considering the tumor progression, we started a 3 rd -line chemotherapy by weekly paclitaxel leading to a durable disease control. As the patient presented an isolated, pre-sacral lymph node progression, she underwent a stereotactic body radiotherapy (SBRT) that allowed a tumor complete response. At a follow up of more than 2 years, the patient is alive, in good clinical conditions and tumor-free. Conclusions This case highlights the importance of an individualized, multidisciplinary management strategy for GCVUC. The prolonged weekly paclitaxel may offer durable disease control in selected patients with a good tolerability. However, the addition of a targeted local treatment, such as SBRT, probably contributed to its efficacy. Further studies are warranted to establish evidence-based guidelines for this aggressive variant. Giant cell carcinoma urothelial carcinoma bladder cancer chemotherapy stereotactic radiotherapy Figures Figure 1 Background The urothelial carcinoma represents the predominant histological subtype of bladder cancer [ 1 ]. The giant cell variant (GCVUC), a rare subtype, is histologically characterized by pleomorphic, multinucleated giant tumor cells and is associated with an aggressive clinical behavior and a poor prognosis [ 2 – 4 ]. To date, only a few cases have been described in the literature [ 2 ]. Due to the lack of consolidated clinical data, the optimal treatment approach is not clearly defined [ 3 – 5 ]. We present the case of a patient with a metastatic GCVUC showing a durable, complete tumor response to a 3rd line weekly paclitaxel associated with a stereotactic body radiotherapy (SBRT). Case Presentation In September 2019, a Caucasian, 52-year-old no-smoker woman, presented with pelvic pain and macroscopic hematuria. She had no relevant comorbities. The clinical examination was normal. The performance status (ECOG) was 0. The blood analyses were in the normal ranges. The cystoscopy revealed a lesion of the bladder base and another one of the right hemitrigone. The histology was consisted with a high-grade muscle-invasive urothelial carcinoma with an unusual component of approximately 80% of multinucleated giant cells, associated with vascular tumor emboli and an aspect of carcinoma in situ [ Fig. 1 ]. At Immunohistochemistry, tumor cells were positive for GATA-3 [ Fig. 2 ] and negative for CD68 and β-HCG. The whole body CT scan showed the presence of a large bladder tumor lesion involving the trigone, the lateral wall, and the dome with an infiltration of the distal right ureter [ Fig. 3 ] resulting in upstream dilatation of the right urinary tract, the multiple lymph nodes of 6 mm in the left external iliac region, of 8 mm in the right external iliac region, and in the left latero-aortic and inter-aorto-caval region. No distant metastases were documented. The patient received four cycles of neoadjuvant dose-dense chemotherapy by the MVAC regimen (methotrexate, vinblastine, doxorubicin, cisplatin) from October to December 2019. In January 2020, after a radiologic tumor evaluation demonstrating a partial tumor regression, the patient underwent anterior pelvic exenteration including a radical cystectomy with hysterectomy, bilateral oophorectomy, extended pelvic lymphadenectomy and ileal conduit urinary diversion. The histology confirmed the presence of residual high-grade GCVUC infiltrating the muscularis propria and the peri vesical adipose tissue, without any lymph node involvement (0/16). Given the advanced disease stage, the high-grade histological features, and the elevated risk of recurrence, the case was reviewed by a multidisciplinary team, which recommended adjuvant systemic therapy. However, the patient declined the proposed treatment. The subsequent CT scan revealed the appearance of a 5 mm suspicious pulmonary lesion of the right lower lobe, a heterogeneous left external iliac lymphadenopathy measuring 31 × 29 mm, a moderate progression of the bilateral pyelocaliceal dilation (19 mm on the right, 18 mm on the left), with minimal calyceal dilatation; and a progression of a small left renal hilar lymphadenopathy (10 × 17 mm vs 9 × 13 mm). In May 2020, the 18 Fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG-PET/CT scan) confirmed the presence of a metastatic disease [ Fig. 4a-b ]. Systemic chemotherapy with a Cisplatin/Gemcitabine combined protocol was started but quickly discontinued due to a disease progression [ Fig. 5a-b ]. From August to December 2020, the patient received a 2nd -line immunotherapy treatment with Pembrolizumab resulting in a mixed response on the 18 F-FDG-PET/CT scan, with a partial regression of the lung metastasis but a progression of the nodal disease [ Fig. 6a-b ]. From January 2021 to October 2022, we also administered a 3rd -line chemotherapy by weekly paclitaxel. The 18 F-FDG-PET/CT scan of May 2022 demonstrated a complete metabolic response in both pulmonary and nodal sites but a slow progression of a pelvic presacral peritoneal lesion of 12 mm of diameter [ Fig. 7 ]. Based on these dissociated radiological results with an isolated oligoprogression, the patient continued the chemotherapy and a stereotactic body radiotherapy (SBRT) was delivered in May 2022 (35 Gy in 5 fractions) to the presacral lesion, leading to a complete, tumor metabolic response, confirmed by the following radiological controls. At the follow-up visit of April 2025, the patient was asymptomatic, in good general condition and tumor-free as confirmed by the 18 F-FDG-PET/CT scan of March 2025 [ Fig. 8a-b ]. Discussion Giant cell variant urothelial carcinoma (GCVUC), a rare but aggressive histopathological subtype of bladder cancer [ 2 , 3 ], is often diagnosed at advanced stage and shows a poor overall prognosis [ 6 , 7 ]. Histologically, GCVUC presents with aggregates or sheets of highly pleomorphic, giant cells with variable tumor necrosis and cellular cohesion but its diagnosis is challenging as it may overlap with other rare bladder subtypes including osteoclast-like giant cell carcinoma, syncytiotrophoblastic giant cell carcinoma, sarcomatoid carcinoma or giant cell tumors of other origins [ 8 , 9 ]. Immunohistochemistry plays a pivotal role to confirm the correct diagnosis as the expression of GATA3, an urothelial lineage marker, supports the urothelial origin [ 8 , 9 ]. The presence of vascular emboli and carcinoma in situ , as observed in our case, confirms the high tumor aggressiveness as reported in the litterature [ 2 ]. No standardized treatment protocols exist due to the limited data but a multimodal approach combining surgery, systemic chemotherapy, and immunotherapy appears reasonable [ 10 , 11 ]. In our case, the use of a neoadjuvant dose-dense MVAC chemotherapy before the radical surgery was extrapolated from conventional urothelial carcinoma guidelines, aiming to improve resectability and survival [ 12 ]. Our case highlights the potential benefit of a 3rd line prolonged weekly taxane-based chemotherapy in achieving durable disease control in patients with metastatic GCVUC. Despite the aggressive nature of this histologic variant and the failure of prior treatment lines, the patient experienced a prolonged radiological tumor response with a good tolerability and quality of life. As the patient showed an isolated tumor oligoprogression, we administered the SBRT to treat this lesion, resistant to the chemotherapy. This combined strategy probably contributed to the prolonged tumor control optimizing the disease management. This case highlights the importance of an individualized treatment strategy and the potential efficacy of a weekly taxane-based chemotherapy in maintaining a long-term remission in selected patients, even if pretreated . Future studies should focus on the molecular characterization of GCVUC to identify potential therapeutic targets [ 8 ]. Finally, larger data are essential to define the optimal management strategies and improve the patient outcome. Conclusions GCVUC remains a rare and aggressive bladder cancer subtype with limited clinical data. This case highlights the potential of a personalized, multimodal approach integrating systemic chemotherapy, particularly a weekly taxane-based regimen, and targeted local treatments, such as SBRT, to achieve meaningful long-term disease control, even in metastatic and pretreated patients. Given the poor prognosis typically associated with GCVUC, further studies and larger case series are needed to better define optimal therapeutic strategies and to explore the potential role of molecular characterization in guiding treatment decisions. Abbreviations GCVUC Giant cell variant of urothelial carcinoma SBRT Stereotactic body radiotherapy MVAC Methotrexate, vinblastine, doxorubicin, cisplatin 18 F-FDG-PET/CT scan 18 Fluorodeoxyglucose positron emission tomography/computed tomography Declarations Ethics approval and consent to participate The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in the study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Consent to publication A written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal. Availability of data and materials All data and materials are available for review at the Division of Medical Oncology, CHR Metz-Thionville, in an electronic format. Competing interest The authors declare that they have no competing interests. Funding : Not applicable. Authors’ contributions The patient was admitted under the care of RL andunderwent systemic treatment by RL, MC, FP, JE, POL, GRO and DDL. Radiological imaging was obtained with permission bythe radiological department at CHR Metz-Thionville. Histology pictures were courteously done by Dr Nathalie Marcon ofthe radiological department at CHR Metz-Thionville. All authors substantially contributed to conception, acquisition, analysis and interpretation of data. All authors have been involved in drafting, revising and approving the final manuscript. Acknowledgements Dr Nathalie Marcon ofthe radiological department at CHR Metz-Thionville for histology and immunohistochemistry pictures. Reporting Checklist statement The authors have completed the CARE reporting checklist that is included as a separate file. References Antoni S, Ferlay J, Soerjomataram I, Znaor A, Jemal A, Bray F. Bladder cancer incidence and mortality: a global overview and recent trends. Eur Urol. 2017;71(1):96–108. 10.1016/j.eururo.2016.06.010 . PMID:27370177. Portugal-Gaspar F, Lopez-Beltran A, Paner GP, Blanca A, Gómez EG, Montironi R, Cimadamore A, Bilé A, Volavšek M, Cheng L. Giant cell carcinoma of the urinary bladder: clinicopathologic analysis and oncological outcomes. Virchows Arch. 2024;485(3):535–46. 10.1007/s00428-024-03858-w . Epub 2024 Jul 18. PMID: 39023556; PMCID: PMC11415457. Baydar D, Amin MB, Epstein JI. Osteoclast-rich undifferentiated carcinomas of the urinary tract. Mod Pathol. 2006;19(2):161 – 71. 10.1038/modpathol.3800521 . PMID: 16322750. LopezBeltran A, Luque RJ, Cheng L. Histologic variants of urothelial carcinoma: differential diagnosis and clinical implications. Hum Pathol. 2018;71:13–27. 10.1016/j.humpath.2017.10.015 . Amin MB. Histological variants of urothelial carcinoma: diagnostic, therapeutic and prognostic implications. Mod Pathol. 2009;22 Suppl 2:S96-S118. 10.1038/modpathol.2009.26 . PMID: 19494856. Lopez-Beltran A, Blanca A, Montironi R, Cheng L, Regueiro JC. Pleomorphic giant cell carcinoma of the urinary bladder. Hum Pathol. 2009;40(10):1461–6. 10.1016/j.humpath.2009.02.016 . Epub 2009 May 20. PMID: 19467692. Samaratunga H, Delahunt B, Egevad L, Adamson M, Hussey D, Malone G, Hoyle K, Nathan T, Kerle D, Ferguson P, Nacey JN. Pleomorphic giant cell carcinoma of the urinary bladder: an extreme form of tumour de-differentiation. Histopathology. 2016;68(4):533 – 40. 10.1111/his.12785 . Epub 2015 Sep 22. PMID: 26211928. Lopez-Beltran A, Henriques V, Montironi R, Cimadamore A, Raspollini MR, Cheng L. Variants and new entities of bladder cancer. Histopathology. 2019;74(1):77–96. 10.1111/his.13752 . PMID: 30565299. Gulinac M, Velikova T, Dikov D. Multinucleated giant cells of bladder mucosa are modified telocytes: Diagnostic and immunohistochemistry algorithm and relation to PD-L1 expression score. World J Clin Cases. 2023;11(26):6091–104. 10.12998/wjcc.v11.i26.6091 . PMID: 37731584; PMCID: PMC10507540. Seiler R, Ashab HAD, Erho N, et al. Impact of molecular subtypes in muscle-invasive bladder cancer on neoadjuvant chemotherapy response. Eur Urol. 2017;72(4):544–54. 10.1016/j.eururo.2017.05.046 . Keegan KA, Resnick MJ, Clark PE. Multimodal therapies for muscle-invasive urothelial carcinoma of the bladder. Curr Opin Oncol. 2012;24(3):278–83. 10.1097/CCO.0b013e3283510587 . PMID: 22273550; PMCID: PMC3698482. Witjes JA, et al. European Association of Urology guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2023 guidelines. Eur Urol. 2024;85(1):17–31. 10.1016/j.eururo.2023.08.016 . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 19 Sep, 2025 Reviewers agreed at journal 15 Sep, 2025 Reviewers agreed at journal 08 Sep, 2025 Reviewers invited by journal 29 Aug, 2025 Editor assigned by journal 28 Aug, 2025 Editor invited by journal 08 Aug, 2025 Submission checks completed at journal 07 Aug, 2025 First submitted to journal 07 Aug, 2025 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-7162421","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":509813590,"identity":"ead3828d-6be7-4967-a874-9ce598f96076","order_by":0,"name":"Gaia Rachele Oliva","email":"","orcid":"","institution":"Catholic University","correspondingAuthor":false,"prefix":"","firstName":"Gaia","middleName":"Rachele","lastName":"Oliva","suffix":""},{"id":509813591,"identity":"19129833-1d2d-433d-9c34-d162f1fb48c2","order_by":1,"name":"Davide Leo","email":"","orcid":"","institution":"Catholic University","correspondingAuthor":false,"prefix":"","firstName":"Davide","middleName":"","lastName":"Leo","suffix":""},{"id":509813592,"identity":"8a1b6cd9-ebda-46d7-a96b-ce0fb54dadf7","order_by":2,"name":"Marco Campitiello","email":"","orcid":"","institution":"“CHR Metz-Thionville”","correspondingAuthor":false,"prefix":"","firstName":"Marco","middleName":"","lastName":"Campitiello","suffix":""},{"id":509813593,"identity":"5042d7a7-149f-4582-b5b3-196e766d922a","order_by":3,"name":"Francesca Plastino","email":"","orcid":"","institution":"“CHR Metz-Thionville”","correspondingAuthor":false,"prefix":"","firstName":"Francesca","middleName":"","lastName":"Plastino","suffix":""},{"id":509813594,"identity":"ead5f4d7-6af6-4bff-9ab1-20b0f0d8eb83","order_by":4,"name":"Julie Egea","email":"","orcid":"","institution":"“CHR Metz-Thionville”","correspondingAuthor":false,"prefix":"","firstName":"Julie","middleName":"","lastName":"Egea","suffix":""},{"id":509813595,"identity":"bb13c2b6-3313-4314-bf32-71d7590b6816","order_by":5,"name":"Pierre-Olivier Legros","email":"","orcid":"","institution":"“CHR Metz-Thionville”","correspondingAuthor":false,"prefix":"","firstName":"Pierre-Olivier","middleName":"","lastName":"Legros","suffix":""},{"id":509813596,"identity":"0bbf8d97-41a0-4045-aa26-ef8159e724b2","order_by":6,"name":"Raffaele Longo","email":"data:image/png;base64,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","orcid":"","institution":"“CHR Metz-Thionville”","correspondingAuthor":true,"prefix":"","firstName":"Raffaele","middleName":"","lastName":"Longo","suffix":""}],"badges":[],"createdAt":"2025-07-19 06:53:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7162421/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7162421/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90879714,"identity":"dec5bb8d-f075-4a62-83c4-c45215f0a1a9","added_by":"auto","created_at":"2025-09-09 09:36:40","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":181080,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTimeline of tumor diagnosis and treatment.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1: \u003c/strong\u003eHigh-grade muscle-invasive urothelial carcinoma with an unusual component of approximately 80% of multinucleated giant cells, vascular emboli, associated with urothelial carcinoma \u003cem\u003ein situ\u003c/em\u003e (histology; H\u0026amp;E stain, 100x).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2:\u003c/strong\u003e Tumor cells were positive for GATA-3 (Immunohistochemistry, 200x).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3:\u003c/strong\u003e Bladder lesion of the bladder wall (red arrow)\u003cstrong\u003e \u003c/strong\u003e(whole body CT-scan: pelvic axial section).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4a: \u003c/strong\u003eMultiple hypermetabolic lymphadenopathies in the latero-aortic, pre-sacral region, and bilateral external iliac region (red arrows) (\u003csup\u003e 18\u003c/sup\u003eF-FDG-PET/CT: pelvic axial section).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4b: \u003c/strong\u003eSeveral hypermetabolic lymphadenopathies in the right interbronchial and subcarinal region (red arrows) (\u003csup\u003e18\u003c/sup\u003eF-FDG-PET/CT: thoracic axial section).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e5a-b\u003c/strong\u003e: Tumor radiological progression after the 1\u003csup\u003est\u003c/sup\u003e line chemotherapy and before starting immunotherapy (red arrows) (\u003csup\u003e18\u003c/sup\u003eF-FDG-PET/CT: pelvic (\u003cstrong\u003ea\u003c/strong\u003e) and thoracic (\u003cstrong\u003eb\u003c/strong\u003e) axial section).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e6a-b: \u003c/strong\u003eMorphological stability with partial metabolic regression of the left obturator lymph node metastasis (\u003cstrong\u003ea\u003c/strong\u003e) and progression of bilateral mediastinal lymphadenopathies (\u003cstrong\u003eb\u003c/strong\u003e) (red arrows) (\u003csup\u003e18\u003c/sup\u003eF-FDG-PET/CT: pelvic (\u003cstrong\u003ea\u003c/strong\u003e) and thoracic (\u003cstrong\u003eb\u003c/strong\u003e) axial section).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e7: \u003c/strong\u003eSlowly morphological progression of a hypermetabolic presacral pelvic lesion (red arrow) during weekly paclitaxel chemotherapy and before the SBRT treatment (\u003csup\u003e18\u003c/sup\u003eF-FDG-PET/CT: pelvic (\u003cstrong\u003ea\u003c/strong\u003e) and thoracic (\u003cstrong\u003eb\u003c/strong\u003e) axial section).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e8a-b: \u003c/strong\u003eProlonged tumor complete response\u003cstrong\u003e \u003c/strong\u003eat the radiological control of March 2025\u003cstrong\u003e (\u003c/strong\u003e\u003csup\u003e18\u003c/sup\u003eF-FDG-PET/CT: pelvic (\u003cstrong\u003ea\u003c/strong\u003e) and thoracic (\u003cstrong\u003eb\u003c/strong\u003e) axial section).\u003c/p\u003e","description":"","filename":"Figure1AN.png","url":"https://assets-eu.researchsquare.com/files/rs-7162421/v1/72e34a3ee7cc85ed56e3d0a4.png"},{"id":90881517,"identity":"be3b3a50-08c2-4878-a39a-bf5794b9e695","added_by":"auto","created_at":"2025-09-09 09:44:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":722646,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7162421/v1/1f157f6f-8201-46a7-ba85-992f6a8838f6.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eMetastatic Giant Cell Bladder Variant of Urothelial Carcinoma: Description of a rare Case Report successfully treated by a 3 rd line chemotherapy with weekly paclitaxel\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eThe urothelial carcinoma represents the predominant histological subtype of bladder cancer [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The giant cell variant (GCVUC), a rare subtype, is histologically characterized by pleomorphic, multinucleated giant tumor cells and is associated with an aggressive clinical behavior and a poor prognosis [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. To date, only a few cases have been described in the literature [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Due to the lack of consolidated clinical data, the optimal treatment approach is not clearly defined [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. We present the case of a patient with a metastatic GCVUC showing a durable, complete tumor response to a 3rd line weekly paclitaxel associated with a stereotactic body radiotherapy (SBRT).\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eIn September 2019, a Caucasian, 52-year-old no-smoker woman, presented with pelvic pain and macroscopic hematuria. She had no relevant comorbities. The clinical examination was normal. The performance status (ECOG) was 0. The blood analyses were in the normal ranges. The cystoscopy revealed a lesion of the bladder base and another one of the right hemitrigone. The histology was consisted with a high-grade muscle-invasive urothelial carcinoma with an unusual component of approximately 80% of multinucleated giant cells, associated with vascular tumor emboli and an aspect of carcinoma \u003cem\u003ein situ\u003c/em\u003e [\u003cb\u003eFig.\u0026nbsp;1\u003c/b\u003e]. At Immunohistochemistry, tumor cells were positive for GATA-3 [\u003cb\u003eFig.\u0026nbsp;2\u003c/b\u003e] and negative for CD68 and β-HCG. The whole body CT scan showed the presence of a large bladder tumor lesion involving the trigone, the lateral wall, and the dome with an infiltration of the distal right ureter [\u003cb\u003eFig.\u0026nbsp;3\u003c/b\u003e] resulting in upstream dilatation of the right urinary tract, the multiple lymph nodes of 6 mm in the left external iliac region, of 8 mm in the right external iliac region, and in the left latero-aortic and inter-aorto-caval region. No distant metastases were documented. The patient received four cycles of neoadjuvant dose-dense chemotherapy by the MVAC regimen (methotrexate, vinblastine, doxorubicin, cisplatin) from October to December 2019. In January 2020, after a radiologic tumor evaluation demonstrating a partial tumor regression, the patient underwent anterior pelvic exenteration including a radical cystectomy with hysterectomy, bilateral oophorectomy, extended pelvic lymphadenectomy and ileal conduit urinary diversion. The histology confirmed the presence of residual high-grade GCVUC infiltrating the muscularis propria and the peri vesical adipose tissue, without any lymph node involvement (0/16). Given the advanced disease stage, the high-grade histological features, and the elevated risk of recurrence, the case was reviewed by a multidisciplinary team, which recommended adjuvant systemic therapy. However, the patient declined the proposed treatment. The subsequent CT scan revealed the appearance of a 5 mm suspicious pulmonary lesion of the right lower lobe, a heterogeneous left external iliac lymphadenopathy measuring 31 \u0026times; 29 mm, a moderate progression of the bilateral pyelocaliceal dilation (19 mm on the right, 18 mm on the left), with minimal calyceal dilatation; and a progression of a small left renal hilar lymphadenopathy (10 \u0026times; 17 mm \u003cem\u003evs\u003c/em\u003e 9 \u0026times; 13 mm). In May 2020, the \u003csup\u003e18\u003c/sup\u003eFluorodeoxyglucose positron emission tomography/computed tomography (\u003csup\u003e18\u003c/sup\u003eF-FDG-PET/CT scan) confirmed the presence of a metastatic disease [\u003cb\u003eFig.\u0026nbsp;4a-b\u003c/b\u003e]. Systemic chemotherapy with a Cisplatin/Gemcitabine combined protocol was started but quickly discontinued due to a disease progression [\u003cb\u003eFig.\u0026nbsp;5a-b\u003c/b\u003e]. From August to December 2020, the patient received a 2nd -line immunotherapy treatment with Pembrolizumab resulting in a mixed response on the \u003csup\u003e18\u003c/sup\u003eF-FDG-PET/CT scan, with a partial regression of the lung metastasis but a progression of the nodal disease [\u003cb\u003eFig.\u0026nbsp;6a-b\u003c/b\u003e]. From January 2021 to October 2022, we also administered a 3rd -line chemotherapy by weekly paclitaxel. The \u003csup\u003e18\u003c/sup\u003eF-FDG-PET/CT scan of May 2022 demonstrated a complete metabolic response in both pulmonary and nodal sites but a slow progression of a pelvic presacral peritoneal lesion of 12 mm of diameter [\u003cb\u003eFig.\u0026nbsp;7\u003c/b\u003e]. Based on these dissociated radiological results with an isolated oligoprogression, the patient continued the chemotherapy and a stereotactic body radiotherapy (SBRT) was delivered in May 2022 (35 Gy in 5 fractions) to the presacral lesion, leading to a complete, tumor metabolic response, confirmed by the following radiological controls. At the follow-up visit of April 2025, the patient was asymptomatic, in good general condition and tumor-free as confirmed by the \u003csup\u003e18\u003c/sup\u003eF-FDG-PET/CT scan of March 2025 [\u003cb\u003eFig.\u0026nbsp;8a-b\u003c/b\u003e].\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eGiant cell variant urothelial carcinoma (GCVUC), a rare but aggressive histopathological subtype of bladder cancer [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], is often diagnosed at advanced stage and shows a poor overall prognosis [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eHistologically, GCVUC presents with aggregates or sheets of highly pleomorphic, giant cells with variable tumor necrosis and cellular cohesion but its diagnosis is challenging as it may overlap with other rare bladder subtypes including osteoclast-like giant cell carcinoma, syncytiotrophoblastic giant cell carcinoma, sarcomatoid carcinoma or giant cell tumors of other origins [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Immunohistochemistry plays a pivotal role to confirm the correct diagnosis as the expression of GATA3, an urothelial lineage marker, supports the urothelial origin [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The presence of vascular emboli and carcinoma \u003cem\u003ein situ\u003c/em\u003e, as observed in our case, confirms the high tumor aggressiveness as reported in the litterature [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eNo standardized treatment protocols exist due to the limited data but a multimodal approach combining surgery, systemic chemotherapy, and immunotherapy appears reasonable [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In our case, the use of a neoadjuvant dose-dense MVAC chemotherapy before the radical surgery was extrapolated from conventional urothelial carcinoma guidelines, aiming to improve resectability and survival [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eOur case highlights the potential benefit of a 3rd line prolonged weekly taxane-based chemotherapy in achieving durable disease control in patients with metastatic GCVUC. Despite the aggressive nature of this histologic variant and the failure of prior treatment lines, the patient experienced a prolonged radiological tumor response with a good tolerability and quality of life. As the patient showed an isolated tumor oligoprogression, we administered the SBRT to treat this lesion, resistant to the chemotherapy. This combined strategy probably contributed to the prolonged tumor control optimizing the disease management.\u003c/p\u003e\u003cp\u003eThis case highlights the importance of an individualized treatment strategy and the potential efficacy of a weekly taxane-based chemotherapy in maintaining a long-term remission in selected patients, even if pretreated .\u003c/p\u003e\u003cp\u003eFuture studies should focus on the molecular characterization of GCVUC to identify potential therapeutic targets [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Finally, larger data are essential to define the optimal management strategies and improve the patient outcome.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eGCVUC remains a rare and aggressive bladder cancer subtype with limited clinical data. This case highlights the potential of a personalized, multimodal approach integrating systemic chemotherapy, particularly a weekly taxane-based regimen, and targeted local treatments, such as SBRT, to achieve meaningful long-term disease control, even in metastatic and pretreated patients. Given the poor prognosis typically associated with GCVUC, further studies and larger case series are needed to better define optimal therapeutic strategies and to explore the potential role of molecular characterization in guiding treatment decisions.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eGCVUC\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eGiant cell variant of urothelial carcinoma\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eSBRT\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eStereotactic body radiotherapy\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eMVAC\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMethotrexate, vinblastine, doxorubicin, cisplatin\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003csup\u003e\u003cb\u003e18\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eF-FDG-PET/CT scan\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003e\u003csup\u003e18\u003c/sup\u003eFluorodeoxyglucose positron emission tomography/computed tomography\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in the study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data and materials are available for review at the Division of Medical Oncology, CHR Metz-Thionville, in an electronic format.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe patient was admitted under the care of \u003cstrong\u003eRL\u0026nbsp;\u003c/strong\u003eandunderwent systemic treatment by \u003cstrong\u003eRL, MC, FP, JE, POL, GRO and DDL.\u0026nbsp;\u003c/strong\u003eRadiological imaging was obtained with permission bythe radiological department at CHR Metz-Thionville. Histology pictures were courteously done by Dr Nathalie Marcon ofthe radiological department at CHR Metz-Thionville. All authors substantially contributed to conception, acquisition, analysis and interpretation of data. All authors have been involved in drafting, revising and approving the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDr Nathalie Marcon ofthe radiological department at CHR Metz-Thionville for histology and immunohistochemistry pictures.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eReporting Checklist statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have completed the CARE reporting checklist that is included as a separate file.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAntoni S, Ferlay J, Soerjomataram I, Znaor A, Jemal A, Bray F. 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PMID: 26211928.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLopez-Beltran A, Henriques V, Montironi R, Cimadamore A, Raspollini MR, Cheng L. Variants and new entities of bladder cancer. Histopathology. 2019;74(1):77\u0026ndash;96. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/his.13752\u003c/span\u003e\u003cspan address=\"10.1111/his.13752\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 30565299.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGulinac M, Velikova T, Dikov D. Multinucleated giant cells of bladder mucosa are modified telocytes: Diagnostic and immunohistochemistry algorithm and relation to PD-L1 expression score. World J Clin Cases. 2023;11(26):6091\u0026ndash;104. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.12998/wjcc.v11.i26.6091\u003c/span\u003e\u003cspan address=\"10.12998/wjcc.v11.i26.6091\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 37731584; PMCID: PMC10507540.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSeiler R, Ashab HAD, Erho N, et al. Impact of molecular subtypes in muscle-invasive bladder cancer on neoadjuvant chemotherapy response. Eur Urol. 2017;72(4):544\u0026ndash;54. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.eururo.2017.05.046\u003c/span\u003e\u003cspan address=\"10.1016/j.eururo.2017.05.046\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKeegan KA, Resnick MJ, Clark PE. Multimodal therapies for muscle-invasive urothelial carcinoma of the bladder. Curr Opin Oncol. 2012;24(3):278\u0026ndash;83. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/CCO.0b013e3283510587\u003c/span\u003e\u003cspan address=\"10.1097/CCO.0b013e3283510587\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 22273550; PMCID: PMC3698482.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWitjes JA, et al. European Association of Urology guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2023 guidelines. Eur Urol. 2024;85(1):17\u0026ndash;31. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.eururo.2023.08.016\u003c/span\u003e\u003cspan address=\"10.1016/j.eururo.2023.08.016\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"bmc-urology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"buro","sideBox":"Learn more about [BMC Urology](http://bmcurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/buro/default.aspx","title":"BMC Urology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Giant cell carcinoma, urothelial carcinoma, bladder cancer, chemotherapy, stereotactic radiotherapy","lastPublishedDoi":"10.21203/rs.3.rs-7162421/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7162421/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe giant cell variant of urothelial carcinoma (GCVUC) is an exceptionally rare and highly aggressive histologic subtype of bladder cancer, histologically characterized by pleomorphic multinucleated giant cells. Due to the lack of clinical data, its clinical behavior and optimal management remain poorly defined.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe report the case of a Caucasian, 52-year-old, no-smoker woman presenting with pelvic pain and hematuria and diagnosed with a locally advanced GCVUC. The patient initially received a neoadjuvant dose-dense MVAC chemotherapy followed by anterior pelvic exenteration with a pathological partial response. After metastatic recurrence, she underwent two lines of systemic therapy, including cisplatin/gemcitabine chemotherapy and immunotherapy. Considering the tumor progression, we started a 3\u003csup\u003erd\u003c/sup\u003e-line chemotherapy by weekly paclitaxel leading to a durable disease control. As the patient presented an isolated, pre-sacral lymph node progression, she underwent a stereotactic body radiotherapy (SBRT) that allowed a tumor complete response. At a follow up of more than 2 years, the patient is alive, in good clinical conditions and tumor-free.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis case highlights the importance of an individualized, multidisciplinary management strategy for GCVUC. The prolonged weekly paclitaxel may offer durable disease control in selected patients with a good tolerability. However, the addition of a targeted local treatment, such as SBRT, probably contributed to its efficacy. Further studies are warranted to establish evidence-based guidelines for this aggressive variant.\u003c/p\u003e","manuscriptTitle":"Metastatic Giant Cell Bladder Variant of Urothelial Carcinoma: Description of a rare Case Report successfully treated by a 3 rd line chemotherapy with weekly paclitaxel","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-09 09:36:35","doi":"10.21203/rs.3.rs-7162421/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2025-09-19T16:32:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"180808788231608857138321164835919640375","date":"2025-09-15T11:02:05+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"144125028611987750610421397394141582159","date":"2025-09-08T12:58:38+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-29T09:18:45+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-28T06:46:07+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-08-08T12:12:38+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-07T16:26:32+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Urology","date":"2025-08-07T16:23:43+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-urology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"buro","sideBox":"Learn more about [BMC Urology](http://bmcurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/buro/default.aspx","title":"BMC Urology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c9e9e8da-18b7-4f33-b357-7cfe7a46b93e","owner":[],"postedDate":"September 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-09-09T09:36:35+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-09 09:36:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7162421","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7162421","identity":"rs-7162421","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}