A Case Series: High PD-L1 Expression and Postoperative Immunotherapy Response in Four Cases of Sarcomatoid Urothelial Carcinoma

A Case Series: High PD-L1 Expression and Postoperative Immunotherapy Response in Four Cases of Sarcomatoid Urothelial Carcinoma | 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 A Case Series: High PD-L1 Expression and Postoperative Immunotherapy Response in Four Cases of Sarcomatoid Urothelial Carcinoma Haosong Ma, Quanlyu Xu, Donglin He, Guorun Zi, Changxing Ke This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8567844/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 Urothelial carcinoma with sarcomatoid differentiation (UCSD) is a rare and highly aggressive variant with a dismal prognosis. While immune checkpoint inhibitors (ICIs) have revolutionized treatment for advanced urothelial carcinoma, data on PD-L1 expression and its therapeutic implications in UCSD remain scarce. This case series describes four patients with upper tract UCSD who underwent radical surgery. Pathological examination confirmed tumors with diverse morphologies and, notably, high PD-L1 expression [Combined Positive Score (CPS) 30–90 or Tumor Proportion Score (TPS) 80%]. All patients received adjuvant ICI therapy (e.g., Toripalimab) based on their PD-L1 status. With a median follow-up of 18 months, all patients remain alive and disease-free, demonstrating favorable treatment responses. This series enriches the understanding of UCSD and highlights the potential therapeutic guidance value of PD-L1 testing in this aggressive subtype, providing a basis for individualized management. Urothelial carcinoma Sarcomatoid differentiation Carcinosarcoma PD-L1 Immunotherapy Upper tract urothelial carcinoma Case series Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Urothelial carcinoma with sarcomatoid differentiation (UCSD), a rare (0.3%-0.6%) and highly aggressive variant of urothelial carcinoma (UC), is characterized by a biphasic morphology of malignant epithelial and spindle-cell components and portends a significantly worse prognosis than conventional UC, with 5-year cancer-specific survival rates of only 37%-69.1%( 1 , 2 , 3 , 4 ). Radical surgery is the cornerstone for localized disease, yet UCSD responds poorly to conventional platinum-based chemotherapy, posing a major therapeutic challenge( 8 ). The advent of immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis has transformed the landscape for advanced UC, where high PD-L1 expression serves as a predictive biomarker for ICI efficacy( 9 ) ; however, data on PD-L1 expression patterns and the utility of immunotherapy in the unique UCSD subtype are extremely limited. This report presents a series of four upper tract UCSD cases exhibiting remarkably high PD-L1 expression. By integrating detailed clinicopathological features, molecular profiles, and outcomes following PD-L1-guided adjuvant ICI therapy, alongside a pertinent literature review, we aim to systematically delineate the characteristics of UCSD, explore the implications of its prevalent PD-L1 expression, and share successful management experience, thereby emphasizing the critical role of precise biomarker assessment in guiding treatment for this refractory disease. Case Reports Case 1 A 66-year-old male was admitted due to "recurrent painless gross hematuria for over 2 years, with recent aggravation for more than 10 days." The patient experienced intermittent hematuria without obvious cause 2 years prior, with small blood clots and necrotic tissue in the urine. Previous external CT scans showed no definitive urinary tract abnormalities. Ten days before admission, hematuria recurred, accompanied by persistent dull pain in the mid-upper abdomen. Non-contrast abdominal CT upon admission suggested left hydronephrosis with patchy soft tissue shadows, indicating a possible mass (FIGURE 1A). The patient had a history of diabetes mellitus with fair glycemic control. Attempted ureteroscopy for diagnosis failed due to ureteral stenosis. Urine cytology from renal pelvis washing revealed atypical urothelial cells, suggestive of neoplastic lesions. After multidisciplinary discussion and thorough communication with the patient and family, radical surgery was decided. The patient underwent "laparoscopic left nephroureterectomy + hilar lymph node dissection" under general anesthesia. A cauliflower-like mass was observed in the left renal pelvis intraoperatively. Postoperative pathology showed: high-grade urothelial carcinoma of the left renal pelvis, focally with glandular, sarcomatoid, and osteoclast-like giant cell differentiation; tumor infiltration into the renal parenchyma; carcinoma metastasis in 1 out of 6 hilar lymph nodes (1/6). IHC showed tumor cells positive for CK7(+), CK5/6(+), GATA3(+), P63(+), Urop-III(+), Her-2(3+), Ki-67(50%), P53(+), and negative for CK20(-); PD-L1 Combined Positive Score (CPS) was 30. The final pathological diagnosis and staging were: high-grade urothelial carcinoma of the left renal pelvis with sarcomatoid and giant cell differentiation (pT3N1Mx). Microscopically, the tumor exhibited biphasic differentiation, with admixture of epithelioid and spindle-shaped sarcomatoid areas, along with scattered multinucleated osteoclast-like giant cells (FIGURE 2A, FIGURE 3A). The patient recovered well postoperatively. Given high PD-L1 expression and positive lymph node status, adjuvant immunotherapy with Toripalimab was initiated at the 4th postoperative week. During regular follow-up to date (24 months), the patient is in good condition, with no evidence of tumor recurrence or metastasis on periodic imaging. Case 2 A 55-year-old female presented with "painless gross hematuria for 1 month, aggravated with fatigue for 2 weeks." She had intermittent total gross hematuria one month prior, worsening over the past two weeks. CT urography (CTU) revealed a mass at the right pelvi-ureteric junction, highly suggestive of urothelial carcinoma, accompanied by moderate hydronephrosis and hydroureter of the right upper tract (FIGURE 1B). MRI further confirmed the mass at the right ureteropelvic junction. Renal dynamic imaging showed moderately impaired right renal function (GFR 13.52 ml/min). The patient had a history of hysterectomy and appendectomy. After detailed discussion regarding the necessity and risks of surgery, the patient opted for radical surgery. She underwent "laparoscopic right nephroureterectomy + bladder cuff excision." Postoperative pathology indicated: high-grade invasive urothelial carcinoma of the right ureter, sarcomatoid subtype, with tumor invasion into the muscularis propria. Microscopy showed a mixture of high-grade urothelial carcinoma components and markedly atypical spindle sarcomatoid cells (FIGURE 2B, FIGURE 3B). IHC showed tumor cell expression of CK7(+), VIM(+), GATA3(focally weak+), Ki-67(up to 90%), P53(+), Her-2(1+), and negative for CK20(-); mismatch repair proteins were intact (pMMR); PD-L1 CPS was as high as 90. The final diagnosis was: high-grade invasive urothelial carcinoma (sarcomatoid subtype) of the right ureter (pT2N0M0). The patient developed transient intestinal obstruction and moderate anemia postoperatively, which resolved with conservative management. Based on the extremely high PD-L1 expression, adjuvant therapy with "Toripalimab + Vedicitumab" was initiated at the 5th postoperative week. After 18 months of regular treatment and follow-up, the patient tolerates treatment well with no evidence of disease recurrence. Case 3 A 69-year-old male was admitted for "right lower abdominal pain for over 1 month." The patient experienced persistent right lower abdominal pain one month prior, without gross hematuria. Urine cytology revealed suspicious malignant cells, favoring urothelial carcinoma. Pelvic CT showed wall thickening and enhancement of the distal right ureter near the bladder inlet, with upstream ureteral dilation and hydronephrosis (FIGURE 1C). Ureteroscopic biopsy pathology and supplementary IHC supported the diagnosis of high-grade urothelial carcinoma. The patient had a history of benign prostatic hyperplasia. After discussion, radical surgery was performed. The patient underwent "laparoscopic right nephroureterectomy." Postoperative pathology reported: (right ureter) sarcomatoid urothelial carcinoma (microsatellite stable, MSS), with tumor invading through the full thickness of the ureteral wall into the peritureteral fat, accompanied by multiple intravascular tumor thrombi; (right kidney) infiltration of sarcomatoid urothelial carcinoma into the renal parenchyma. Microscopically, the tumor consisted predominantly of densely arranged spindle sarcomatoid cells with significant atypia and frequent mitotic FIGUREs (FIGURE 2C, FIGURE 3C). IHC showed tumor cell expression of VIM(+), GATA3(partial+), CK7(partial+), CKL(partial+), Ki-67(70%), and negative for CK20(-); PD-L1 CPS was 90. The final diagnosis was: sarcomatoid urothelial carcinoma of the right ureter and renal pelvis (pT3NxMx). Considering the advanced pathological stage and high PD-L1 expression, the patient received postoperative Toripalimab immunotherapy. During 15 months of regular follow-up, the patient remains disease-stable with no local recurrence or distant metastasis. Case 4 A 52-year-old female presented with "left flank pain for 2 weeks." The pain started two weeks prior, without hematuria. CT scans from an external hospital and our institution both revealed a large, irregular, exophytic soft tissue mass in the left kidney, measuring approximately 11.3 × 9.6 cm, showing mild heterogeneous enhancement. The mass was poorly demarcated from the lower pole of the spleen, suggesting invasion (FIGURE 1D). The patient had a history of hypertension, pulmonary sarcoidosis, and left renal cysts. Multidisciplinary consultation involving hepatobiliary surgery assessed a high probability of malignancy with invasion of adjacent organs. After detailed discussion of the condition, surgical extent (possibly requiring splenectomy), and risks, the patient underwent "laparoscopic left radical nephrectomy + total splenectomy." Postoperative pathology showed: invasive sarcomatoid urothelial carcinoma of the left kidney, tumor diameter 11 cm, invading the spleen. Microscopically, the tumor was predominantly composed of spindle cell sarcomatoid morphology, with densely packed cells arranged in fascicles and showing infiltrative growth (FIGURE 2D, FIGURE 3D). IHC played a key role in differential diagnosis: tumor cells expressed GATA3 (partial+), CKH (+), CKL (+), VIM (+), while renal lineage markers PAX-8 (-), PAX-2 (-), and CAIX (partial+) were negative, confirming urothelial origin and ruling out sarcomatoid renal cell carcinoma (FIGURE 2H). Separate PD-L1 IHC (clone ELL3N) showed a high Tumor Cell Positive Proportion Score (TPS) of 80%, but a Combined Positive Score (CPS) of < 1. The final staging was: sarcomatoid urothelial carcinoma with splenic invasion (pT4N0Mx). Despite the low CPS score, considering the very high tumor cell PD-L1 expression (80%) and advanced local invasion (pT4), postoperative Toripalimab therapy was initiated. The patient recovered well postoperatively. Regular follow-up for 12 months to date shows no signs of recurrence. Table 1 Summary of Clinicopathological, Therapeutic, and Follow-up Characteristics of Four Patients with Urothelial Carcinoma and Sarcomatoid Differentiation Characteristic Case 1 Case 2 Case 3 Case 4 Age/Sex 66/Male 55/Female 69/Male 52/Female Main Symptom Recurrent hematuria, abdominal pain Gross hematuria Right lower abdominal pain Left flank pain Tumor Location Left renal pelvis Right ureter (pelvi-ureteric junction) Right ureter (distal) Left kidney Imaging Features Renal pelvis soft tissue mass, hydronephrosis Pelvi-ureteric junction mass, hydronephrosis Distal ureteral wall thickening/enhancement, upstream hydroureter Large exophytic renal mass, splenic invasion Surgical Procedure Nephroureterectomy + lymph node dissection Nephroureterectomy + bladder cuff excision Nephroureterectomy Nephrectomy + splenectomy Histology High-grade UC with glandular, sarcomatoid, and giant cell differentiation High-grade UC, sarcomatoid subtype Sarcomatoid urothelial carcinoma Sarcomatoid urothelial carcinoma Key IHC Markers CK7+, GATA3+, P63+, Her-2(3+), CK20(-), Ki-67 50% CK7+, VIM+, GATA3(weak+), CK20(-), Ki-67 90% VIM+, GATA3(partial+), CK7(partial+), CKL(partial+), CK20(-), Ki-67 70% GATA3(partial+), CKH+, CKL+, VIM+; PAX8-, PAX2- PD-L1 Status CPS = 30 CPS = 90 CPS = 90 TPS = 80% (CPS < 1) Final Pathologic Diagnosis & Stage UC with sarcomatoid & giant cell differentiation (pT3N1Mx) UC, sarcomatoid subtype (pT2N0M0) Sarcomatoid UC (pT3NxMx) Sarcomatoid UC with splenic invasion (pT4N0Mx) Postoperative Adjuvant Therapy Toripalimab Toripalimab + Vedicitumab Toripalimab Toripalimab Follow-up Time (months) 24 18 15 12 CPS: Combined Positive Score; TPS: Tumor Proportion Score; UC: Urothelial Carcinoma. Review of related literature Clinical Features Sarcomatoid urothelial carcinoma (SUC) is a rare and highly aggressive malignant bladder tumor, accounting for approximately 0.3%--0.6% of all bladder cancers( 2 , 10 ). It shows a distinct demographic preference, predominantly affecting elderly males, with a median age at diagnosis between 66 and 72 years and a male-to-female ratio of about 3:1( 2 , 3 ). Smoking is a well-established major risk factor. The most common clinical presentation is painless gross hematuria, which may be accompanied by lower urinary tract symptoms such as dysuria, frequency, and urgency( 11 ). Due to its inherently high aggressive biological behavior, most patients present with muscle-invasive (≥ pT2) or even locally advanced disease at initial diagnosis, often with lymph node or distant metastasis( 4 , 12 ). Our case series aligns with this, as all patients were diagnosed at pT2 stage or higher, with Case 1 showing lymph node metastasis. The prognosis of SUC is extremely poor and significantly worse than that of conventional UC. Reported 5-year cancer-specific survival (CSS) rates range from 37% to 69.1%, with a median overall survival (OS) of approximately 14 to 22.5 months( 3 , 4 , 12 ). Regarding treatment, radical surgery is the cornerstone for localized disease. However, SUC responds poorly to platinum-based neoadjuvant or adjuvant chemotherapy, which has not demonstrated a clear survival benefit( 8 , 13 ). Consequently, clinical management is highly challenging, necessitating the exploration of new effective therapeutic strategies. Imaging Features While imaging findings of SUC are not pathognomonic, multimodal imaging can reveal its aggressive features and aid in clinical staging. Ultrasound typically shows a solid, broad-based mass within the bladder lumen or upper urinary tract, with heterogeneous echotexture and abundant blood flow signals. Non-contrast computed tomography (CT) demonstrates an irregular soft-tissue density mass, often with necrosis and cystic changes. Contrast-enhanced CT shows marked and heterogeneous enhancement, with an average diameter often exceeding 3 cm. CT is the preferred method for assessing local invasion and distant metastasis. Magnetic resonance imaging (MRI), with its superior soft tissue resolution, outperforms CT in accurately evaluating tumor invasion depth (e.g., distinguishing T2 from T3 stages) and invasion of surrounding organs. On positron emission tomography-computed tomography (PET-CT), SUC exhibits high metabolic activity, with significantly increased fluorodeoxyglucose (FDG) uptake in primary and metastatic sites, with maximum standardized uptake values (SUVmax) potentially as high as 22.1. This is valuable for detecting occult metastases and comprehensive staging( 10 ). The CT findings in our series (e.g., heterogeneous enhancement, invasion of surrounding structures) are consistent with these aggressive imaging features. Pathological Features Pathological diagnosis of SUC integrates gross, histological, and immunohistochemical findings. Grossly, tumors are typically large (avg. 4–6 cm), polypoid or nodular with a broad base, and the cut surface frequently shows extensive hemorrhage, necrosis, and cystic degeneration( 6 ). Histologically, the defining biphasic morphology comprises malignant epithelial components (usually high-grade urothelial carcinoma, sometimes with squamous or glandular features) admixed with malignant mesenchymal-like (sarcomatoid) areas. The sarcomatoid component most often presents as a high-grade spindle cell sarcoma; special morphological variants include myxoid change or heterologous differentiation, such as osteosarcoma or chondrosarcoma( 6 , 14 ). Our cases reflect this spectrum: Case 1 displayed sarcomatoid areas with osteoclast-like giant cells, Cases 2 and 3 were predominantly composed of sarcomatoid spindle cells, and Case 4 was a massive, sarcomatoid-dominant neoplasm. Immunohistochemically, the epithelial component is strongly positive for Pan-CK, CK7, CK20, EMA, and p63, while GATA-3 expression is variable (~ 16–44%) and often focal or weak( 15 ), as seen in our Cases 2–4. The sarcomatoid component is consistently vimentin-positive (~ 100%), and the critical diagnostic feature is the frequent co-expression of cytokeratins (notably CK AE1/AE3) within these spindle cells, which distinguishes SUC from pure sarcomas( 7 )—a pattern confirmed in all our cases where sarcomatoid areas co-expressed epithelial markers (CK7, CKL, CKH) and vimentin. Notably, sarcomatoid areas show significantly higher infiltration of CD163 + M2-type tumor-associated macrophages compared to epithelial regions( 15 ). The Ki-67 proliferation index is typically very high (> 60–70%), underscoring the tumor's aggressive biology( 10 ), which aligns with the 50–90% Ki-67 indices in our series. A key diagnostic pitfall is the limited tissue from transurethral or ureteroscopic biopsies, which can lead to sampling error and misdiagnosis( 16 ), exemplified by the initial non-diagnostic biopsy in Case 1 and highlighting the need for deep sampling and evaluation of radical specimens. Beyond tumor stage, the proportion of the sarcomatoid component (> 50%) is an important independent prognostic factor associated with worse outcomes( 3 ). Advances in Molecular Understanding Recent years have seen growing insights into the pathogenesis of SUC. SUC is considered the "final common pathway" of urothelial carcinoma dedifferentiation through epithelial-mesenchymal transition (EMT)( 17 ). EMT confers migratory, invasive, and stem cell-like properties to cancer cells. Utilizing digital spatial analysis technology, it has been found that SUC areas exhibit significantly richer tumor stroma infiltration, predominantly composed of CD163 + M2 macrophages and activated fibroblasts, which play immunosuppressive and tumor-promoting roles( 15 ). Gene expression levels of transforming growth factor-beta (TGF-β) are significantly upregulated in SUC areas. TGF-β is a core cytokine driving EMT, creating a microenvironmental loop that promotes tumor invasion and immune evasion( 15 ). This may partially explain the observed high PD-L1 expression in our case series. Differential Diagnosis Urothelial carcinoma with sarcomatoid differentiation (UCSD) requires meticulous differentiation from other spindle cell lesions of the upper urinary tract, relying on histomorphology combined with a systematic immunohistochemical (IHC) panel( 7 , 20 ). FIGURE 4 provides a diagnostic algorithm outlining the key steps. The principal differential diagnoses include: Sarcomatoid renal cell carcinoma (sRCC) : This represents the most critical differential, particularly for renal parenchymal tumors. sRCC retains a renal phenotype, typically showing strong expression of renal lineage markers such as PAX8, PAX2, and CAIX, while urothelial markers (e.g., GATA3, p63) are generally negative( 17 ).In our series, Case 4 was distinguished from sRCC based on PAX8/PAX2 negativity and focal GATA3 positivity. Primary mesenchymal sarcomas : Examples include leiomyosarcoma and fibrosarcoma. These are inherently mesenchymal neoplasms and thus are cytokeratin (CK) negative, while expressing vimentin and lineage-specific markers (e.g., SMA, Desmin)( 7 ). Inflammatory myofibroblastic tumor (IMT) : A potentially low-grade malignant tumor more common in younger patients, characterized by a proliferation of spindle-shaped myofibroblasts within an inflammatory background. Approximately 50% of cases express ALK, while CK is typically negative( 19 ). Sarcomatoid carcinoma from other origins or metastases : Invasion or metastasis from sarcomatoid carcinomas of the prostate, colorectum, or gynecological tract must be excluded through clinical context and specific markers (e.g., PSA, CDX2, PAX8/WT-1)( 7 ). A Systematic Diagnostic Approach: For an upper tract spindle cell lesion, a stepwise diagnostic strategy is recommended( 20 ): Initiate with CK/Pan-CK staining to confirm epithelial differentiation. If positive, determine the primary site using a combination of GATA3/p63 (urothelial) and PAX8/PAX2 (renal). If CK is negative, mesenchymal tumors are favored, prompting evaluation for ALK, SMA, and other markers. Regardless of the final diagnosis, assessment of PD-L1 (reporting both CPS and TPS is advised) and mismatch repair (MMR) protein status is strongly recommended for therapeutic guidance. Treatment and Prognosis Owing to its rarity and aggressive nature, no standard treatment regimen for sarcomatoid urothelial carcinoma (SUC) exists based on large prospective trials, and its management generally follows principles for muscle-invasive urothelial carcinoma guided by retrospective evidence( 8 ). Radical surgery with lymph node dissection remains the cornerstone for potentially curative treatment of localized disease and offers superior outcomes compared to organ-preserving approaches( 10 , 24 ). However, SUC demonstrates poor sensitivity to conventional platinum-based chemotherapy, with neither neoadjuvant nor adjuvant chemotherapy conferring a clear survival benefit( 8 , 13 ); radiotherapy provides limited local control, and treatment options for metastatic SUC remain scarce with dismal outcomes. The prognosis of SUC is exceedingly poor, with 5-year cancer-specific survival rates ranging from 37% to 69.1%( 3 , 4 ) and a median overall survival of approximately 14 to 22.5 months in radically treated localized cases( 3 , 10 ). Prognosis is heterogeneous and influenced by key determinants including advanced pathological stage (≥ pT3) and lymph node involvement, surgical margin status (with R0 resection being paramount), a sarcomatoid component exceeding 50% (an independent risk factor for diminished survival( 3 , 5 )), and the presence of heterologous differentiation (e.g., osteosarcomatous) which may indicate more aggressive behavior( 14 ). Our case series highlights the frequent occurrence of high PD-L1 expression in SUC (CPS 30–90 or TPS up to 80%), a phenomenon potentially linked to its immunosuppressive tumor microenvironment characterized by M2 macrophage infiltration and activated TGF-β signaling( 15 ). Previous reports have documented heterogeneous responses to immune checkpoint inhibitors in sarcomatoid urothelial carcinoma( 21 ). In contrast, all patients in our series received adjuvant ICI therapy based on PD-L1 status and remain disease-free at a median follow-up of 18 months, providing compelling preliminary evidence supporting postoperative immunotherapy for UCSD patients with high PD-L1 expression. Notably, PD-L1 assessment requires contextual interpretation: in tumors dominated by sarcomatoid morphology with sparse tumor-infiltrating lymphocytes, the Combined Positive Score (CPS) may underestimate the immunogenic potential of tumor cells, whereas the Tumor Proportion Score (TPS) may more accurately reflect PD-L1 expression levels, as illustrated in Case 4. Therefore, we advocate for simultaneous reporting of both CPS and TPS in the pathological assessment of UCSD to inform comprehensive clinical decision-making. Patient Perspective Upon diagnosis of this rare and aggressive cancer, all patients experienced significant anxiety. The multidisciplinary explanation that their postoperative treatment would be guided by personalized PD-L1 testing—rather than a standard approach—provided substantial reassurance and hope. Patients have tolerated immunotherapy well and express profound relief at remaining disease-free during follow-up. Written informed consent has been obtained from all participants for publication of their anonymized details and this perspective. Limitations This study is a retrospective case series analysis with a small sample size, dictated by the rarity of the disease. PD-L1 testing utilized different clones (e.g., MXR003 and ELL3N), and scoring systems (CPS vs. TPS) varied among cases. This reflects the current state of biomarker assessment in clinical practice and underscores the need for more standardized testing and reporting protocols in the future. Although patients in this series demonstrated favorable short-term outcomes with immunotherapy, longer-term survival benefits and potential late toxicities require further extended follow-up for validation. Conclusion We report four cases of upper tract urothelial carcinoma with sarcomatoid differentiation (UCSD) exhibiting high PD-L1 expression. All patients received radical surgery followed by adjuvant immune checkpoint inhibitor therapy guided by PD-L1 testing results. With a median follow-up of 18 months, all patients remain disease-free, demonstrating favorable treatment responses. Integrated with literature analysis, this series indicates that UCSD is a rare, aggressive tumor with a poor prognosis. Its diagnosis relies on recognizing biphasic histological differentiation and key differential diagnosis from other spindle cell tumors, particularly sarcomatoid renal cell carcinoma, via immunohistochemistry (especially co-expression of CK and Vimentin). The prevalent high PD-L1 expression in our cases reveals its potential association with an immunosuppressive tumor microenvironment and the EMT process. We emphasize that for suspected UCSD cases, adequate pathological sampling and systematic IHC analysis (recommended panel: CK, GATA3, p63, Vimentin, PAX8, PAX2, etc.) are essential. We strongly recommend incorporating PD-L1 testing (reporting both CPS and TPS) into the routine pathological evaluation of UCSD, as this helps identify patients who may benefit from immunotherapy. The positive follow-up results in our series provide preliminary clinical evidence supporting the use of postoperative adjuvant immunotherapy for UCSD patients with high PD-L1 expression. Future multicenter, prospective studies with larger cohorts are needed to define the molecular landscape of UCSD, validate the predictive value of PD-L1 and other biomarkers, and explore optimal strategies combining surgery, chemotherapy, immunotherapy, and targeted therapy to ultimately improve the long-term clinical outcomes for these patients. Declarations Data Availability Statement The original contributions presented in the study are included in the article and supplementary material. Further inquiries can be directed to the corresponding author. Ethics Statement The studies involving human participants were reviewed and approved by the Ethics Committee of the Second Affiliated Hospital of Kunming Medical University. Informed consent to participate was obtained from all participants. All procedures performed in this study were in accordance with the ethical standards of the institutional and/ or national research committee and with the 1964 Helsinki Declaration and its later amendments. Written informed consent was obtained from all participants for the publication of any potentially identifiable data included in this article. Author Contributions H-SM and Q-LX: Investigation, Writing – original draft, Writing – review & editing. D-LH: Resources, Writing – review & editing. G-RZ: Writing – review & editing. C-XK: Supervision, Writing – review & editing. Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Generative AI Statement The author(s) declare that no Generative AI was used in the creation of this manuscript. Funding The author(s) declare that financial support was received for the research and/or publication of this article. Yunnan health training project of high level talents (Approval Number: H-2024017); Yunnan Fundamental Research Projects (grant NO.202501AT070489); Yunnan Fundamental Research Kunming Medical University Joint Projects (grant NO.202401AY070001-080). Clinical Trial Registration Clinical trial number: Not applicable. References Humphrey PA, Moch H, Cubilla AL, et al. The 2016 WHO classification of tumours of the urinary system and male genital organs-part B: prostate and bladder tumours. Eur Urol. 2016;70(1):106–19. Robinson SP, Farooq A, Laniado M, Motiwala H, Karim O. The demographic features, clinical outcomes, prognosis and treatment options for patients with sarcomatoid carcinoma of the urinary bladder: a single centre experience. Int Braz J Urol. 2018;44(1):45–52. Liu S, Yao Y, Wang ZK, et al. 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Accuracy of Transurethral Resection of the Bladder in Detecting Variant Histology of Bladder Cancer Compared with Radical Cystectomy. Eur Urol Focus. 2022;8(1):189–96. Sharma P, Callahan MK, Bono P, et al. Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial. Lancet Oncol. 2016;17(11):1590–8. Mohan BP, Gupta A, Jain A, et al. Sarcomatoid Carcinoma of Renal Pelvis Involving Ureter and Renal Parenchyma with Heterologous Osteosarcomatous Differentiation: A Case Report and Review of Literature. Iran J Pathol. 2018;13(3):369–74. Tappero S, Panunzio A, Hohenhorst L, et al. Radical cystectomy in non-metastatic sarcomatoid bladder cancer: A direct comparison to urothelial bladder cancer. Eur J Surg Oncol. 2023;49(1):27–33. Wang J, Gillaspie C, Kunadharaju R, Talmon GA, Enke C. Sarcomatoid urothelial carcinoma: A single cancer center experience. World J Oncol. 2011;2(4):175–80. Diamantopoulos LN, Makrakis D, Korentzelos D et al. Development and validation of a prognostic nomogram for overall and disease-specific survival in patients with sarcomatoid urothelial carcinoma. Urol Oncol. 2023;41(6):296.e19-296.e26. 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-8567844","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":583562246,"identity":"bd391480-d83f-4ff6-b7b7-acfe5a386676","order_by":0,"name":"Haosong Ma","email":"","orcid":"","institution":"Second Affiliated Hospital of Kunming Medical College","correspondingAuthor":false,"prefix":"","firstName":"Haosong","middleName":"","lastName":"Ma","suffix":""},{"id":583562247,"identity":"12e65940-143b-49f4-b7b5-0247f838d487","order_by":1,"name":"Quanlyu Xu","email":"","orcid":"","institution":"Second Affiliated Hospital of Kunming Medical College","correspondingAuthor":false,"prefix":"","firstName":"Quanlyu","middleName":"","lastName":"Xu","suffix":""},{"id":583562248,"identity":"74383bbe-8ecc-4e8f-9733-0cda24eade2a","order_by":2,"name":"Donglin He","email":"","orcid":"","institution":"Second Affiliated Hospital of Kunming Medical College","correspondingAuthor":false,"prefix":"","firstName":"Donglin","middleName":"","lastName":"He","suffix":""},{"id":583562249,"identity":"629cd4d6-10dc-4be9-a70c-8deebd4aacc5","order_by":3,"name":"Guorun Zi","email":"","orcid":"","institution":"Second Affiliated Hospital of Kunming Medical College","correspondingAuthor":false,"prefix":"","firstName":"Guorun","middleName":"","lastName":"Zi","suffix":""},{"id":583562250,"identity":"971ff888-ae86-4df0-a67e-670c8e0182f4","order_by":4,"name":"Changxing Ke","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAw0lEQVRIiWNgGAWjYBACCTBpYCPHz8x88AEJWgrSjCXb2ZINSNDy4XCiwXkeMwGitEi29x578MGAOcH4MIMZA0ONTTRBLdI859INZxiw5ZkdZkh7wHAsLbeBkBY5iRwzaR4DnmKgluMGjA2HidAi/8ZM+o+BROLmZsY2CaK0SEvwmEkzGBgkbmBmZiNOi2RPjplkj0GCscRhNmaDBGL8InH8jJnEjz//5fj7z3988KHGhrAWVJBAmvJRMApGwSgYBbgAAC8bOKkJDA8BAAAAAElFTkSuQmCC","orcid":"","institution":"Second Affiliated Hospital of Kunming Medical College","correspondingAuthor":true,"prefix":"","firstName":"Changxing","middleName":"","lastName":"Ke","suffix":""}],"badges":[],"createdAt":"2026-01-10 11:09:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8567844/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8567844/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":101787178,"identity":"60133c19-470d-4fd1-90a5-8cbf916cc104","added_by":"auto","created_at":"2026-02-03 15:45:39","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":152906,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8567844/v1/946ca0ad3618cece7f93f7f0.png"},{"id":101787179,"identity":"f461b3e3-f4f6-45d6-9845-e8bf19e53a43","added_by":"auto","created_at":"2026-02-03 15:45:39","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":82164,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8567844/v1/2b2f4d7f698047df676dfd87.jpg"},{"id":101787177,"identity":"797be033-daf2-485b-89b3-18327c5db03d","added_by":"auto","created_at":"2026-02-03 15:45:39","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":104465,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8567844/v1/0178c930365c565c59ce2b08.jpg"},{"id":101787180,"identity":"eedab5a9-b8ae-4e73-9c4d-c54c45876a6c","added_by":"auto","created_at":"2026-02-03 15:45:39","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":208148,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8567844/v1/07a076adb8506d1bd915fb65.png"},{"id":108084708,"identity":"b680f0f7-9649-4f55-91e5-a5c2f931110f","added_by":"auto","created_at":"2026-04-29 08:25:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":786536,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8567844/v1/8a25b9d3-69e6-46a6-ae2e-102b9ec76c43.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A Case Series: High PD-L1 Expression and Postoperative Immunotherapy Response in Four Cases of Sarcomatoid Urothelial Carcinoma","fulltext":[{"header":"Introduction","content":"\u003cp\u003eUrothelial carcinoma with sarcomatoid differentiation (UCSD), a rare (0.3%-0.6%) and highly aggressive variant of urothelial carcinoma (UC), is characterized by a biphasic morphology of malignant epithelial and spindle-cell components and portends a significantly worse prognosis than conventional UC, with 5-year cancer-specific survival rates of only 37%-69.1%(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Radical surgery is the cornerstone for localized disease, yet UCSD responds poorly to conventional platinum-based chemotherapy, posing a major therapeutic challenge(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). The advent of immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis has transformed the landscape for advanced UC, where high PD-L1 expression serves as a predictive biomarker for ICI efficacy(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003csup\u003e;\u003c/sup\u003e however, data on PD-L1 expression patterns and the utility of immunotherapy in the unique UCSD subtype are extremely limited. This report presents a series of four upper tract UCSD cases exhibiting remarkably high PD-L1 expression. By integrating detailed clinicopathological features, molecular profiles, and outcomes following PD-L1-guided adjuvant ICI therapy, alongside a pertinent literature review, we aim to systematically delineate the characteristics of UCSD, explore the implications of its prevalent PD-L1 expression, and share successful management experience, thereby emphasizing the critical role of precise biomarker assessment in guiding treatment for this refractory disease.\u003c/p\u003e"},{"header":"Case Reports","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eCase 1\u003c/h2\u003e \u003cp\u003eA 66-year-old male was admitted due to \"recurrent painless gross hematuria for over 2 years, with recent aggravation for more than 10 days.\" The patient experienced intermittent hematuria without obvious cause 2 years prior, with small blood clots and necrotic tissue in the urine. Previous external CT scans showed no definitive urinary tract abnormalities. Ten days before admission, hematuria recurred, accompanied by persistent dull pain in the mid-upper abdomen. Non-contrast abdominal CT upon admission suggested left hydronephrosis with patchy soft tissue shadows, indicating a possible mass (FIGURE 1A). The patient had a history of diabetes mellitus with fair glycemic control. Attempted ureteroscopy for diagnosis failed due to ureteral stenosis. Urine cytology from renal pelvis washing revealed atypical urothelial cells, suggestive of neoplastic lesions. After multidisciplinary discussion and thorough communication with the patient and family, radical surgery was decided. The patient underwent \"laparoscopic left nephroureterectomy + hilar lymph node dissection\" under general anesthesia. A cauliflower-like mass was observed in the left renal pelvis intraoperatively. Postoperative pathology showed: high-grade urothelial carcinoma of the left renal pelvis, focally with glandular, sarcomatoid, and osteoclast-like giant cell differentiation; tumor infiltration into the renal parenchyma; carcinoma metastasis in 1 out of 6 hilar lymph nodes (1/6). IHC showed tumor cells positive for CK7(+), CK5/6(+), GATA3(+), P63(+), Urop-III(+), Her-2(3+), Ki-67(50%), P53(+), and negative for CK20(-); PD-L1 Combined Positive Score (CPS) was 30. The final pathological diagnosis and staging were: high-grade urothelial carcinoma of the left renal pelvis with sarcomatoid and giant cell differentiation (pT3N1Mx). Microscopically, the tumor exhibited biphasic differentiation, with admixture of epithelioid and spindle-shaped sarcomatoid areas, along with scattered multinucleated osteoclast-like giant cells (FIGURE 2A, FIGURE 3A). The patient recovered well postoperatively. Given high PD-L1 expression and positive lymph node status, adjuvant immunotherapy with Toripalimab was initiated at the 4th postoperative week. During regular follow-up to date (24 months), the patient is in good condition, with no evidence of tumor recurrence or metastasis on periodic imaging.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eCase 2\u003c/h3\u003e\n\u003cp\u003eA 55-year-old female presented with \"painless gross hematuria for 1 month, aggravated with fatigue for 2 weeks.\" She had intermittent total gross hematuria one month prior, worsening over the past two weeks. CT urography (CTU) revealed a mass at the right pelvi-ureteric junction, highly suggestive of urothelial carcinoma, accompanied by moderate hydronephrosis and hydroureter of the right upper tract (FIGURE 1B). MRI further confirmed the mass at the right ureteropelvic junction. Renal dynamic imaging showed moderately impaired right renal function (GFR 13.52 ml/min). The patient had a history of hysterectomy and appendectomy. After detailed discussion regarding the necessity and risks of surgery, the patient opted for radical surgery. She underwent \"laparoscopic right nephroureterectomy + bladder cuff excision.\" Postoperative pathology indicated: high-grade invasive urothelial carcinoma of the right ureter, sarcomatoid subtype, with tumor invasion into the muscularis propria. Microscopy showed a mixture of high-grade urothelial carcinoma components and markedly atypical spindle sarcomatoid cells (FIGURE 2B, FIGURE 3B). IHC showed tumor cell expression of CK7(+), VIM(+), GATA3(focally weak+), Ki-67(up to 90%), P53(+), Her-2(1+), and negative for CK20(-); mismatch repair proteins were intact (pMMR); PD-L1 CPS was as high as 90. The final diagnosis was: high-grade invasive urothelial carcinoma (sarcomatoid subtype) of the right ureter (pT2N0M0). The patient developed transient intestinal obstruction and moderate anemia postoperatively, which resolved with conservative management. Based on the extremely high PD-L1 expression, adjuvant therapy with \"Toripalimab + Vedicitumab\" was initiated at the 5th postoperative week. After 18 months of regular treatment and follow-up, the patient tolerates treatment well with no evidence of disease recurrence.\u003c/p\u003e\n\u003ch3\u003eCase 3\u003c/h3\u003e\n\u003cp\u003eA 69-year-old male was admitted for \"right lower abdominal pain for over 1 month.\" The patient experienced persistent right lower abdominal pain one month prior, without gross hematuria. Urine cytology revealed suspicious malignant cells, favoring urothelial carcinoma. Pelvic CT showed wall thickening and enhancement of the distal right ureter near the bladder inlet, with upstream ureteral dilation and hydronephrosis (FIGURE 1C). Ureteroscopic biopsy pathology and supplementary IHC supported the diagnosis of high-grade urothelial carcinoma. The patient had a history of benign prostatic hyperplasia. After discussion, radical surgery was performed. The patient underwent \"laparoscopic right nephroureterectomy.\" Postoperative pathology reported: (right ureter) sarcomatoid urothelial carcinoma (microsatellite stable, MSS), with tumor invading through the full thickness of the ureteral wall into the peritureteral fat, accompanied by multiple intravascular tumor thrombi; (right kidney) infiltration of sarcomatoid urothelial carcinoma into the renal parenchyma. Microscopically, the tumor consisted predominantly of densely arranged spindle sarcomatoid cells with significant atypia and frequent mitotic FIGUREs (FIGURE 2C, FIGURE 3C). IHC showed tumor cell expression of VIM(+), GATA3(partial+), CK7(partial+), CKL(partial+), Ki-67(70%), and negative for CK20(-); PD-L1 CPS was 90. The final diagnosis was: sarcomatoid urothelial carcinoma of the right ureter and renal pelvis (pT3NxMx). Considering the advanced pathological stage and high PD-L1 expression, the patient received postoperative Toripalimab immunotherapy. During 15 months of regular follow-up, the patient remains disease-stable with no local recurrence or distant metastasis.\u003c/p\u003e\n\u003ch3\u003eCase 4\u003c/h3\u003e\n\u003cp\u003eA 52-year-old female presented with \"left flank pain for 2 weeks.\" The pain started two weeks prior, without hematuria. CT scans from an external hospital and our institution both revealed a large, irregular, exophytic soft tissue mass in the left kidney, measuring approximately 11.3 × 9.6 cm, showing mild heterogeneous enhancement. The mass was poorly demarcated from the lower pole of the spleen, suggesting invasion (FIGURE 1D). The patient had a history of hypertension, pulmonary sarcoidosis, and left renal cysts. Multidisciplinary consultation involving hepatobiliary surgery assessed a high probability of malignancy with invasion of adjacent organs. After detailed discussion of the condition, surgical extent (possibly requiring splenectomy), and risks, the patient underwent \"laparoscopic left radical nephrectomy + total splenectomy.\" Postoperative pathology showed: invasive sarcomatoid urothelial carcinoma of the left kidney, tumor diameter 11 cm, invading the spleen. Microscopically, the tumor was predominantly composed of spindle cell sarcomatoid morphology, with densely packed cells arranged in fascicles and showing infiltrative growth (FIGURE 2D, FIGURE 3D). IHC played a key role in differential diagnosis: tumor cells expressed GATA3 (partial+), CKH (+), CKL (+), VIM (+), while renal lineage markers PAX-8 (-), PAX-2 (-), and CAIX (partial+) were negative, confirming urothelial origin and ruling out sarcomatoid renal cell carcinoma (FIGURE 2H). Separate PD-L1 IHC (clone ELL3N) showed a high Tumor Cell Positive Proportion Score (TPS) of 80%, but a Combined Positive Score (CPS) of \u0026lt; 1. The final staging was: sarcomatoid urothelial carcinoma with splenic invasion (pT4N0Mx). Despite the low CPS score, considering the very high tumor cell PD-L1 expression (80%) and advanced local invasion (pT4), postoperative Toripalimab therapy was initiated. The patient recovered well postoperatively. Regular follow-up for 12 months to date shows no signs of recurrence.\u003c/p\u003e \u003cp\u003eTable 1 Summary of Clinicopathological, Therapeutic, and Follow-up Characteristics of Four Patients with Urothelial Carcinoma and Sarcomatoid Differentiation\u003c/p\u003e\u003cp\u003e \u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e\u003ccolgroup cols=\"5\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCase 1\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCase 2\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCase 3\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCase 4\u003c/p\u003e \u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge/Sex\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e66/Male\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55/Female\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e69/Male\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e52/Female\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMain Symptom\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRecurrent hematuria, abdominal pain\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGross hematuria\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRight lower abdominal pain\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLeft flank pain\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTumor Location\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLeft renal pelvis\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRight ureter (pelvi-ureteric junction)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRight ureter (distal)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLeft kidney\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eImaging Features\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRenal pelvis soft tissue mass, hydronephrosis\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePelvi-ureteric junction mass, hydronephrosis\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDistal ureteral wall thickening/enhancement, upstream hydroureter\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLarge exophytic renal mass, splenic invasion\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSurgical Procedure\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNephroureterectomy + lymph node dissection\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNephroureterectomy + bladder cuff excision\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNephroureterectomy\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNephrectomy + splenectomy\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHistology\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHigh-grade UC with glandular, sarcomatoid, and giant cell differentiation\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHigh-grade UC, sarcomatoid subtype\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSarcomatoid urothelial carcinoma\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSarcomatoid urothelial carcinoma\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eKey IHC Markers\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCK7+, GATA3+, P63+, Her-2(3+), CK20(-), Ki-67 50%\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCK7+, VIM+, GATA3(weak+), CK20(-), Ki-67 90%\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eVIM+, GATA3(partial+), CK7(partial+), CKL(partial+), CK20(-), Ki-67 70%\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGATA3(partial+), CKH+, CKL+, VIM+; PAX8-, PAX2-\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePD-L1 Status\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCPS = 30\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCPS = 90\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCPS = 90\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTPS = 80% (CPS \u0026lt; 1)\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFinal Pathologic Diagnosis \u0026amp; Stage\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUC with sarcomatoid \u0026amp; giant cell differentiation (pT3N1Mx)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUC, sarcomatoid subtype (pT2N0M0)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSarcomatoid UC (pT3NxMx)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSarcomatoid UC with splenic invasion (pT4N0Mx)\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePostoperative Adjuvant Therapy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eToripalimab\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eToripalimab + Vedicitumab\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eToripalimab\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eToripalimab\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFollow-up Time (months)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\u003c/div\u003e \u003cp\u003e\u003c/p\u003e \u003cp\u003e \u003cem\u003eCPS: Combined Positive Score; TPS: Tumor Proportion Score; UC: Urothelial Carcinoma.\u003c/em\u003e \u003c/p\u003e"},{"header":"Review of related literature","content":"\u003ch2\u003eClinical Features\u003c/h2\u003e\u003cp\u003eSarcomatoid urothelial carcinoma (SUC) is a rare and highly aggressive malignant bladder tumor, accounting for approximately 0.3%--0.6% of all bladder cancers(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). It shows a distinct demographic preference, predominantly affecting elderly males, with a median age at diagnosis between 66 and 72 years and a male-to-female ratio of about 3:1(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Smoking is a well-established major risk factor. The most common clinical presentation is painless gross hematuria, which may be accompanied by lower urinary tract symptoms such as dysuria, frequency, and urgency(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Due to its inherently high aggressive biological behavior, most patients present with muscle-invasive (≥ pT2) or even locally advanced disease at initial diagnosis, often with lymph node or distant metastasis(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Our case series aligns with this, as all patients were diagnosed at pT2 stage or higher, with Case 1 showing lymph node metastasis. The prognosis of SUC is extremely poor and significantly worse than that of conventional UC. Reported 5-year cancer-specific survival (CSS) rates range from 37% to 69.1%, with a median overall survival (OS) of approximately 14 to 22.5 months(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Regarding treatment, radical surgery is the cornerstone for localized disease. However, SUC responds poorly to platinum-based neoadjuvant or adjuvant chemotherapy, which has not demonstrated a clear survival benefit(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Consequently, clinical management is highly challenging, necessitating the exploration of new effective therapeutic strategies.\u003c/p\u003e\u003ch3\u003eImaging Features\u003c/h3\u003e\u003cp\u003eWhile imaging findings of SUC are not pathognomonic, multimodal imaging can reveal its aggressive features and aid in clinical staging. Ultrasound typically shows a solid, broad-based mass within the bladder lumen or upper urinary tract, with heterogeneous echotexture and abundant blood flow signals. Non-contrast computed tomography (CT) demonstrates an irregular soft-tissue density mass, often with necrosis and cystic changes. Contrast-enhanced CT shows marked and heterogeneous enhancement, with an average diameter often exceeding 3 cm. CT is the preferred method for assessing local invasion and distant metastasis. Magnetic resonance imaging (MRI), with its superior soft tissue resolution, outperforms CT in accurately evaluating tumor invasion depth (e.g., distinguishing T2 from T3 stages) and invasion of surrounding organs. On positron emission tomography-computed tomography (PET-CT), SUC exhibits high metabolic activity, with significantly increased fluorodeoxyglucose (FDG) uptake in primary and metastatic sites, with maximum standardized uptake values (SUVmax) potentially as high as 22.1. This is valuable for detecting occult metastases and comprehensive staging(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). The CT findings in our series (e.g., heterogeneous enhancement, invasion of surrounding structures) are consistent with these aggressive imaging features.\u003c/p\u003e\u003ch3\u003ePathological Features\u003c/h3\u003e\u003cp\u003ePathological diagnosis of SUC integrates gross, histological, and immunohistochemical findings. Grossly, tumors are typically large (avg. 4–6 cm), polypoid or nodular with a broad base, and the cut surface frequently shows extensive hemorrhage, necrosis, and cystic degeneration(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Histologically, the defining biphasic morphology comprises malignant epithelial components (usually high-grade urothelial carcinoma, sometimes with squamous or glandular features) admixed with malignant mesenchymal-like (sarcomatoid) areas. The sarcomatoid component most often presents as a high-grade spindle cell sarcoma; special morphological variants include myxoid change or heterologous differentiation, such as osteosarcoma or chondrosarcoma(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Our cases reflect this spectrum: Case 1 displayed sarcomatoid areas with osteoclast-like giant cells, Cases 2 and 3 were predominantly composed of sarcomatoid spindle cells, and Case 4 was a massive, sarcomatoid-dominant neoplasm. Immunohistochemically, the epithelial component is strongly positive for Pan-CK, CK7, CK20, EMA, and p63, while GATA-3 expression is variable (~ 16–44%) and often focal or weak(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e), as seen in our Cases 2–4. The sarcomatoid component is consistently vimentin-positive (~ 100%), and the critical diagnostic feature is the frequent co-expression of cytokeratins (notably CK AE1/AE3) within these spindle cells, which distinguishes SUC from pure sarcomas(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e)—a pattern confirmed in all our cases where sarcomatoid areas co-expressed epithelial markers (CK7, CKL, CKH) and vimentin. Notably, sarcomatoid areas show significantly higher infiltration of CD163 + M2-type tumor-associated macrophages compared to epithelial regions(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). The Ki-67 proliferation index is typically very high (\u0026gt; 60–70%), underscoring the tumor's aggressive biology(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), which aligns with the 50–90% Ki-67 indices in our series. A key diagnostic pitfall is the limited tissue from transurethral or ureteroscopic biopsies, which can lead to sampling error and misdiagnosis(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e), exemplified by the initial non-diagnostic biopsy in Case 1 and highlighting the need for deep sampling and evaluation of radical specimens. Beyond tumor stage, the proportion of the sarcomatoid component (\u0026gt; 50%) is an important independent prognostic factor associated with worse outcomes(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003ch2\u003eAdvances in Molecular Understanding\u003c/h2\u003e\u003cp\u003eRecent years have seen growing insights into the pathogenesis of SUC. SUC is considered the \"final common pathway\" of urothelial carcinoma dedifferentiation through epithelial-mesenchymal transition (EMT)(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). EMT confers migratory, invasive, and stem cell-like properties to cancer cells. Utilizing digital spatial analysis technology, it has been found that SUC areas exhibit significantly richer tumor stroma infiltration, predominantly composed of CD163 + M2 macrophages and activated fibroblasts, which play immunosuppressive and tumor-promoting roles(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Gene expression levels of transforming growth factor-beta (TGF-β) are significantly upregulated in SUC areas. TGF-β is a core cytokine driving EMT, creating a microenvironmental loop that promotes tumor invasion and immune evasion(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). This may partially explain the observed high PD-L1 expression in our case series.\u003c/p\u003e\u003ch2\u003eDifferential Diagnosis\u003c/h2\u003e\u003cp\u003eUrothelial carcinoma with sarcomatoid differentiation (UCSD) requires meticulous differentiation from other spindle cell lesions of the upper urinary tract, relying on histomorphology combined with a systematic immunohistochemical (IHC) panel(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). FIGURE 4 provides a diagnostic algorithm outlining the key steps.\u003c/p\u003e\u003cp\u003eThe principal differential diagnoses include:\u003c/p\u003e\u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eSarcomatoid renal cell carcinoma (sRCC)\u003c/b\u003e: This represents the most critical differential, particularly for renal parenchymal tumors. sRCC retains a renal phenotype, typically showing strong expression of renal lineage markers such as PAX8, PAX2, and CAIX, while urothelial markers (e.g., GATA3, p63) are generally negative(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).In our series, Case 4 was distinguished from sRCC based on PAX8/PAX2 negativity and focal GATA3 positivity.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003ePrimary mesenchymal sarcomas\u003c/b\u003e: Examples include leiomyosarcoma and fibrosarcoma. These are inherently mesenchymal neoplasms and thus are cytokeratin (CK) negative, while expressing vimentin and lineage-specific markers (e.g., SMA, Desmin)(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eInflammatory myofibroblastic tumor (IMT)\u003c/b\u003e: A potentially low-grade malignant tumor more common in younger patients, characterized by a proliferation of spindle-shaped myofibroblasts within an inflammatory background. Approximately 50% of cases express ALK, while CK is typically negative(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e).\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eSarcomatoid carcinoma from other origins or metastases\u003c/b\u003e: Invasion or metastasis from sarcomatoid carcinomas of the prostate, colorectum, or gynecological tract must be excluded through clinical context and specific markers (e.g., PSA, CDX2, PAX8/WT-1)(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e\u003cp\u003eA Systematic Diagnostic Approach: For an upper tract spindle cell lesion, a stepwise diagnostic strategy is recommended(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e): Initiate with CK/Pan-CK staining to confirm epithelial differentiation. If positive, determine the primary site using a combination of GATA3/p63 (urothelial) and PAX8/PAX2 (renal). If CK is negative, mesenchymal tumors are favored, prompting evaluation for ALK, SMA, and other markers. Regardless of the final diagnosis, assessment of PD-L1 (reporting both CPS and TPS is advised) and mismatch repair (MMR) protein status is strongly recommended for therapeutic guidance.\u003c/p\u003e\u003ch2\u003eTreatment and Prognosis\u003c/h2\u003e\u003cp\u003eOwing to its rarity and aggressive nature, no standard treatment regimen for sarcomatoid urothelial carcinoma (SUC) exists based on large prospective trials, and its management generally follows principles for muscle-invasive urothelial carcinoma guided by retrospective evidence(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Radical surgery with lymph node dissection remains the cornerstone for potentially curative treatment of localized disease and offers superior outcomes compared to organ-preserving approaches(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). However, SUC demonstrates poor sensitivity to conventional platinum-based chemotherapy, with neither neoadjuvant nor adjuvant chemotherapy conferring a clear survival benefit(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e); radiotherapy provides limited local control, and treatment options for metastatic SUC remain scarce with dismal outcomes. The prognosis of SUC is exceedingly poor, with 5-year cancer-specific survival rates ranging from 37% to 69.1%(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) and a median overall survival of approximately 14 to 22.5 months in radically treated localized cases(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Prognosis is heterogeneous and influenced by key determinants including advanced pathological stage (≥ pT3) and lymph node involvement, surgical margin status (with R0 resection being paramount), a sarcomatoid component exceeding 50% (an independent risk factor for diminished survival(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e)), and the presence of heterologous differentiation (e.g., osteosarcomatous) which may indicate more aggressive behavior(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Our case series highlights the frequent occurrence of high PD-L1 expression in SUC (CPS 30–90 or TPS up to 80%), a phenomenon potentially linked to its immunosuppressive tumor microenvironment characterized by M2 macrophage infiltration and activated TGF-β signaling(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Previous reports have documented heterogeneous responses to immune checkpoint inhibitors in sarcomatoid urothelial carcinoma(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). In contrast, all patients in our series received adjuvant ICI therapy based on PD-L1 status and remain disease-free at a median follow-up of 18 months, providing compelling preliminary evidence supporting postoperative immunotherapy for UCSD patients with high PD-L1 expression. Notably, PD-L1 assessment requires contextual interpretation: in tumors dominated by sarcomatoid morphology with sparse tumor-infiltrating lymphocytes, the Combined Positive Score (CPS) may underestimate the immunogenic potential of tumor cells, whereas the Tumor Proportion Score (TPS) may more accurately reflect PD-L1 expression levels, as illustrated in Case 4. Therefore, we advocate for simultaneous reporting of both CPS and TPS in the pathological assessment of UCSD to inform comprehensive clinical decision-making.\u003c/p\u003e\u003ch2\u003ePatient Perspective\u003c/h2\u003e\u003cp\u003eUpon diagnosis of this rare and aggressive cancer, all patients experienced significant anxiety. The multidisciplinary explanation that their postoperative treatment would be guided by personalized PD-L1 testing—rather than a standard approach—provided substantial reassurance and hope. Patients have tolerated immunotherapy well and express profound relief at remaining disease-free during follow-up. Written informed consent has been obtained from all participants for publication of their anonymized details and this perspective.\u003c/p\u003e\u003ch2\u003eLimitations\u003c/h2\u003e\u003cp\u003eThis study is a retrospective case series analysis with a small sample size, dictated by the rarity of the disease. PD-L1 testing utilized different clones (e.g., MXR003 and ELL3N), and scoring systems (CPS vs. TPS) varied among cases. This reflects the current state of biomarker assessment in clinical practice and underscores the need for more standardized testing and reporting protocols in the future. Although patients in this series demonstrated favorable short-term outcomes with immunotherapy, longer-term survival benefits and potential late toxicities require further extended follow-up for validation.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWe report four cases of upper tract urothelial carcinoma with sarcomatoid differentiation (UCSD) exhibiting high PD-L1 expression. All patients received radical surgery followed by adjuvant immune checkpoint inhibitor therapy guided by PD-L1 testing results. With a median follow-up of 18 months, all patients remain disease-free, demonstrating favorable treatment responses. Integrated with literature analysis, this series indicates that UCSD is a rare, aggressive tumor with a poor prognosis. Its diagnosis relies on recognizing biphasic histological differentiation and key differential diagnosis from other spindle cell tumors, particularly sarcomatoid renal cell carcinoma, via immunohistochemistry (especially co-expression of CK and Vimentin). The prevalent high PD-L1 expression in our cases reveals its potential association with an immunosuppressive tumor microenvironment and the EMT process. We emphasize that for suspected UCSD cases, adequate pathological sampling and systematic IHC analysis (recommended panel: CK, GATA3, p63, Vimentin, PAX8, PAX2, etc.) are essential. We strongly recommend incorporating PD-L1 testing (reporting both CPS and TPS) into the routine pathological evaluation of UCSD, as this helps identify patients who may benefit from immunotherapy. The positive follow-up results in our series provide preliminary clinical evidence supporting the use of postoperative adjuvant immunotherapy for UCSD patients with high PD-L1 expression. Future multicenter, prospective studies with larger cohorts are needed to define the molecular landscape of UCSD, validate the predictive value of PD-L1 and other biomarkers, and explore optimal strategies combining surgery, chemotherapy, immunotherapy, and targeted therapy to ultimately improve the long-term clinical outcomes for these patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eData Availability Statement\u003c/p\u003e\n\u003cp\u003eThe original contributions presented in the study are included in the article and supplementary material. Further inquiries can be directed to the corresponding author.\u003c/p\u003e\n\u003cp\u003eEthics Statement\u003c/p\u003e\n\u003cp\u003eThe studies involving human participants were reviewed and approved by the Ethics Committee of the Second Affiliated Hospital of Kunming Medical University.\u0026nbsp;Informed consent to participate was obtained from all participants.\u0026nbsp;All procedures performed in this study were in accordance with the ethical standards of the institutional and/ or national research committee and with the 1964 Helsinki Declaration and its later amendments.\u0026nbsp;Written informed consent was obtained from all participants for the publication of any potentially identifiable data included in this article.\u003c/p\u003e\n\u003cp\u003eAuthor Contributions\u003c/p\u003e\n\u003cp\u003eH-SM and Q-LX: Investigation, Writing \u0026ndash; original draft, Writing \u0026ndash; review \u0026amp; editing. D-LH: Resources, Writing \u0026ndash; review \u0026amp; editing. G-RZ: Writing \u0026ndash; review \u0026amp; editing. C-XK: Supervision, Writing \u0026ndash; review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003eConflict of Interest\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e\n\u003cp\u003eGenerative AI Statement\u003c/p\u003e\n\u003cp\u003eThe author(s) declare that no Generative AI was used in the creation of this manuscript.\u003c/p\u003e\n\u003cp\u003eFunding \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe author(s) declare that financial support was received for the research and/or publication of this article. Yunnan health training project of high level talents (Approval Number: H-2024017); Yunnan Fundamental Research Projects (grant NO.202501AT070489); Yunnan Fundamental Research Kunming Medical University Joint Projects (grant NO.202401AY070001-080).\u003c/p\u003e\n\u003cp\u003eClinical Trial Registration\u003c/p\u003e\n\u003cp\u003eClinical trial number: Not applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHumphrey PA, Moch H, Cubilla AL, et al. The 2016 WHO classification of tumours of the urinary system and male genital organs-part B: prostate and bladder tumours. Eur Urol. 2016;70(1):106\u0026ndash;19.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRobinson SP, Farooq A, Laniado M, Motiwala H, Karim O. The demographic features, clinical outcomes, prognosis and treatment options for patients with sarcomatoid carcinoma of the urinary bladder: a single centre experience. Int Braz J Urol. 2018;44(1):45\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu S, Yao Y, Wang ZK, et al. Prognostic value of the sarcomatoid component in bladder cancer: a propensity score matching study. Oncol Lett. 2023;26(2):344.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWright JL, Black PC, Brown GA, et al. Differences in survival among patients with sarcomatoid carcinoma, carcinosarcoma and urothelial carcinoma of the bladder. J Urol. 2007;178(6):2302\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSanfrancesco J, McKenney JK, Leivo MZ, et al. Sarcomatoid urothelial carcinoma of the bladder: analysis of 28 cases with emphasis on clinicopathologic features and markers of epithelial-to-mesenchymal transition. Arch Pathol Lab Med. 2016;140(6):543\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBaydar D, Amin K, Sangueza O, et al. 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Clin Case Rep. 2024;12:e8761.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePark HS. Sarcomatoid urothelial carcinoma arising in the female urethral diverticulum. J Pathol Transl Med. 2021;55(3):298\u0026ndash;302.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXiao J, Chen H, Ge J, et al. Clinical efficacy analysis of partial cystectomy and radical cystectomy in the treatment of muscle-invasive sarcomatoid carcinoma of the urinary bladder. Front Oncol. 2024;14:1324487.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlmassi N, Vertosick EA, Sjoberg DD, et al. Pathological and oncological outcomes in patients with sarcomatoid differentiation undergoing cystectomy. BJU Int. 2022;129(4):463\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMalla M, Wang JF, Trepeta R, Feng A, Wang J. Sarcomatoid carcinoma of the urinary bladder. 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Sarcomatoid Carcinoma of Renal Pelvis Involving Ureter and Renal Parenchyma with Heterologous Osteosarcomatous Differentiation: A Case Report and Review of Literature. Iran J Pathol. 2018;13(3):369\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTappero S, Panunzio A, Hohenhorst L, et al. Radical cystectomy in non-metastatic sarcomatoid bladder cancer: A direct comparison to urothelial bladder cancer. Eur J Surg Oncol. 2023;49(1):27\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang J, Gillaspie C, Kunadharaju R, Talmon GA, Enke C. Sarcomatoid urothelial carcinoma: A single cancer center experience. World J Oncol. 2011;2(4):175\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDiamantopoulos LN, Makrakis D, Korentzelos D et al. Development and validation of a prognostic nomogram for overall and disease-specific survival in patients with sarcomatoid urothelial carcinoma. Urol Oncol. 2023;41(6):296.e19-296.e26.\u003c/span\u003e\u003c/li\u003e\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":"Urothelial carcinoma, Sarcomatoid differentiation, Carcinosarcoma, PD-L1, Immunotherapy, Upper tract urothelial carcinoma, Case series","lastPublishedDoi":"10.21203/rs.3.rs-8567844/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8567844/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eUrothelial carcinoma with sarcomatoid differentiation (UCSD) is a rare and highly aggressive variant with a dismal prognosis. While immune checkpoint inhibitors (ICIs) have revolutionized treatment for advanced urothelial carcinoma, data on PD-L1 expression and its therapeutic implications in UCSD remain scarce. This case series describes four patients with upper tract UCSD who underwent radical surgery. Pathological examination confirmed tumors with diverse morphologies and, notably, high PD-L1 expression [Combined Positive Score (CPS) 30\u0026ndash;90 or Tumor Proportion Score (TPS) 80%]. All patients received adjuvant ICI therapy (e.g., Toripalimab) based on their PD-L1 status. With a median follow-up of 18 months, all patients remain alive and disease-free, demonstrating favorable treatment responses. This series enriches the understanding of UCSD and highlights the potential therapeutic guidance value of PD-L1 testing in this aggressive subtype, providing a basis for individualized management.\u003c/p\u003e","manuscriptTitle":"A Case Series: High PD-L1 Expression and Postoperative Immunotherapy Response in Four Cases of Sarcomatoid Urothelial Carcinoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-03 15:45:33","doi":"10.21203/rs.3.rs-8567844/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":"868cfb9c-2ccf-4889-815a-09a5092b3634","owner":[],"postedDate":"February 3rd, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Withdrawn","date":"2026-04-29T08:07:19+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-29T08:23:16+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-03 15:45:33","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8567844","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8567844","identity":"rs-8567844","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}