Carcinosarcomas (CSs) are aggressive biphasic tumors characterized by epithelial and mesenchymal components, whose histogenesis and differentiation dynamics remain poorly understood. We present single‐nucleus RNA sequencing (snRNA‐seq) analysis of six CSs (five endometrial and one ovarian) and two normal endometrial samples, profiling over 96,298 cells. By integrating transcriptomic data with inferred copy number variations (CNVs), immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and in situ hybridization (ISH) validation, we resolved the complex cellular architecture of these tumors, identified lineage‐specific programs, and revealed unexpected differentiation trajectories. snRNA‐seq was used to further refine the histopathological classification of three cases by uncovering heterologous differentiation not previously recognized: one rhabdomyogenic, one osteogenic, and, notably, one exhibiting a novel tenogenic program, defined by the expression of SCX, MKX, and TNMD. All CSs displayed a prominent mesenchymal compartment comprising both undifferentiated fibroblast‐like cells and distinct lineage committed populations, including rhabdomyoblasts (Rhab), tenoblasts (Teno), osteoblasts (Osteo), and chondroblasts (Chond). In some tumors, multiple mesenchymal identities co‐existed, and in others, differentiation gradients (e.g. immature versus mature rhabdomyoblasts) were observed. These patterns underscore the cellular plasticity and multilineage potential of the sarcomatous component. Furthermore, the expression of specialized interface markers (COL22A1, NCAM1, ACAN, CHRNG, MUSK) suggests that some tumors use structured developmental programs reminiscent of the muscle–tendon junction, enthesis, or neuromuscular junction. CNV analysis revealed tumor‐specific genomic alterations with clonal and subclonal patterns linked to differentiation state, which were validated by FISH. Altogether, this study demonstrates that CSs are not static biphasic tumors but rather complex ecosystems with extensive developmental plasticity. Our findings redefine their classification and support the use of single‐nucleus approaches to uncover hidden differentiation trajectories in highly heterogeneous cancers, including the discovery of a previously unreported tenogenic lineage. Our results challenge the diagnosis of homologous CS when only morphological criteria are applied. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Efficacy and safety of pembrolizumab with or without lenvatinib in recurrent uterine carcinosarcoma: a real-world single-center study.

Comparison of breast and gastric HER2 immunohistochemistry (IHC) scoring criteria in the assessment of endometrial carcinoma.

Prognostic impact of sarcomatous component in patients with localized and locally advanced uterine carcinosarcoma: a retrospective study in Latin America.

Hyponatremia is a common electrolyte abnormality in patients with malignancy, and recent investigations into the off-label use of SGLT 2 inhibitors for syndrome of inappropriate antidiuretic hormone (SIADH) have shown promising short-term results. We report the case of an 84-year-old woman with history of relapsed metastatic uterine carcinosarcoma with chronic hyponatremia who failed standard therapy. The patient was initiated on empagliflozin 11 months ago and has had sustained normalization of serum sodium levels. While less is known about the long-term use of these agents, this case highlights the potential for SGLT 2 inhibitors to be used as a low-burden therapeutic option for cancer-associated chronic hyponatremia.

Background/Objectives: Although the binarism between type I and II endometrial cancer was dismissed and substituted with molecular classification, histopathological features remain of paramount importance. Hence, analysing survival outcomes according to histological type, our aim is to clarify whether the morphological features of the tumour retain prognostic relevance in the context of advanced disease. Methods: This is a retrospective analysis led within the Thames Valley Cancer Alliance Network. Results: We include 148 FIGO 2009 stage III–IV patients affected by endometrioid endometrial cancer (EEC) G1, G2, and G3, carcinosarcoma (CS), serous carcinoma (SC), and clear cell carcinoma (CCC) of the uterus. Five year overall survival (OS) is distinct among the histological groups (p-value < 0.001), being 73.3% for G2 endometrioid, 49.2% for G3 endometrioid, 8.3% for CS, and 28.4% for SC. The divergence was marked also for 5 year progression-free survival (PFS) (p-value < 0.001) as follows: for G2 endometrioid, was 76.4%; for G3 endometrioid, 52.7%; and for carcinosarcoma, 5.9%. PFS after 18 months for serous carcinoma was 5.7%. The multivariate analysis found G3 endometrioid (HR 2.91, 95% CI 1.20–7.11, p-value 0.018), carcinosarcoma (HR 12.15, 95% CI 5.07–29.11, p-value < 0.001), and serous carcinoma (HR 4.84, 95% CI 2.16–10.83, p-value < 0.001) as independent predictors of poor survival, as well as cervical invasion (HR 1.83, 95% CI 1.10–3.05, p-value 0.020) as the only histopathological feature confirmed. Regarding progression-free only carcinosarcoma (HR 14.91, 95% CI 5.28–41.11) and serous carcinoma (HR 17.68, 95% CI 6.41–48.75) were associated with an increased risk of recurrence. Conclusions: Our findings testify that, beyond the disease stage, histological subtype remains a major determinant of survival outcome. Cervical involvement is associated with a more aggressive disease, possibly correlated to death beyond relapse. Prospective trials involving advanced stage endometrial cancer, stratified by histological subtype and integrated with the molecular classification, are required.

Precision oncology leverages real-world data, essential for identifying biomarkers and therapies. Large language models (LLMs) can aid at structuring unstructured data, overcoming current bottlenecks in precision oncology. We propose a framework for responsible LLM integration into precision oncology, co-developed by multidisciplinary experts and supported by Cancer Core Europe. Five thematic dimensions and ten principles for practice are outlined and illustrated through application to uterine carcinosarcoma in a thought experiment.

PTEN mutation status in uterine carcinosarcomas: A comprehensive overview and a new diagnostic approach.

Feasibility IB trial of paclitaxel/carboplatin + Galunisertib. (a small molecule inhibitor of the kinase domain of type 1 TGF-B receptor) in patients with newly diagnosed, persistent or recurrent carcinosarcoma of the uterus or ovary.

Preoperative molecular classification of endometrial cancer: Validation through biopsy and matched hysterectomy specimens.

Uterine carcinosarcoma (UCS) is a rare but highly aggressive endometrial malignancy with poor prognosis. Optimal management involves a multimodal approach, including surgery followed by adjuvant chemoradiotherapy. Given its rarity, reporting institutional experiences is essential to expand knowledge and improve patient outcomes. This study presents a retrospective analysis of UCS cases managed at a London tertiary centre for Gynaecological Oncology, focusing on perioperative characteristics and survival outcomes. We conducted a retrospective comparative analysis of case series of 45 patients who underwent treatment for UCS at Guy's & St Thomas' NHS Foundation Trust between March 2018 and December 2020. Perioperative characteristics, staging, and treatment modalities were analysed. Kaplan-Meier survival analysis was performed to evaluate overall survival (OS) and progression-free survival (PFS), comparing patients who received adjuvant chemoradiotherapy to those who did not. There was a significant increase in disease stage postoperatively compared to preoperative assessment (p=0.0008). Initially, 30 (68%) and seven (16%) patients were classified as stage I and stage III, respectively. However, final postoperative staging identified 15 (34%) as stage I and 21 (48%) as stage III, highlighting the high rate of upstaging. The mean OS for the cohort was 32.4 months [95% confidence interval (CI)=26.4-38.4]. Kaplan-Meier analysis demonstrated significantly longer OS in patients receiving adjuvant radiotherapy compared to those who did not (mean OS: 39.9 months, 95%CI=30.9-48.8 vs. 26.6 months, 95%CI=19.6-33.6; log-rank p=0.044). Similarly, PFS was significantly improved in patients treated with combined chemoradiotherapy compared to radiotherapy alone (mean PFS: 39.1 months, 95%CI=25.9-52.2 vs. 21.2 months, 95%CI=7.7-34.6; Breslow p=0.02). A multimodal approach, including surgery and adjuvant treatment, improves survival in UCS. High upstaging rates highlight the need for better preoperative assessment and vigilant monitoring. Further research is needed to optimise treatment strategies.

Uterine carcinosarcomas (UCS) are rare and aggressive gynecological tumors and the description of biomarkers that can help guide targeted treatments in this disease is a critical gap in current medical research. This study aims to measure the prevalence of trophoblast cell-surface antigen 2 (Trop-2) and folate receptor alpha (FRα) in UCS and evaluate their prognostic significance. This retrospective analysis examined data from female patients diagnosed with UCS who underwent surgery followed by carboplatin and paclitaxel chemotherapy between January 2012 and December 2020. Tissue microarrays from 89 samples were assessed for Trop-2 and FRα expression by IHC. High positivity was defined as a score of ≥ 50% of tumor cells with strong staining intensity for Trop-2 and ≥ 75% with medium or strong staining intensity for FRα. Sociodemographic and clinical features were analyzed alongside progression-free survival (PFS) and overall survival (OS) outcomes. The mean age at diagnosis was 66.2 years (Standard Deviation, SD: 7) and the mean body mass index was 28.7kg/m² (SD: 6.2). Non-white women accounted for 71.6% of cases. Heterologous subtype corresponded to 63.0% of cases, and lymphovascular invasion was observed in 59.2%. Complete resection (R0) was achieved in 66.3% of cases. High expression of Trop-2 and FRα was found in 49.4% and 17.4% of epithelial components, respectively, with no high positivity in sarcomatous components. Negative margins were more common in stage I/II disease (p = 0.001), and FRα overexpression correlated with Trop-2 overexpression (p = 0.007). On multivariate analysis, advanced stage (p = 0.015) and incomplete resection (p < 0.001) predicted shorter PFS, while both factors also independently worsened OS (p = 0.013 and p = 0.001, respectively). Lymphadenectomy was associated with improved OS (p = 0.025). Complete resection and advanced stage were suggested as prognostic factors in UCS. FRα and Trop-2 are increasingly recognized as therapeutic targets and their elevated expression levels in the epithelial component of UCS are promising, although not associated with prognosis in this cohort.

Background:Uterine carcinosarcoma is a rare gynecological malignancy characterized by high invasiveness and poor prognosis. At present, common treatment methods include surgery, chemotherapy, and radiotherapy. Radiotherapy can induce tumor cells to produce reactive oxygen species through ionizing radiation, leading to damage to intracellular DNA and mediating tumor cell death. Based on this, we identified a novel radiotherapy sensitive gene for predicting the prognosis, immune microenvironment, and drug sensitivity of uterine carcinosarcoma patients.Methods:The Cancer Genome Atlas database was used to obtain genetic and clinical information of patients with uterine carcinosarcoma. A risk scoring model was built using Lasso regression model. In order to enhance the predictive ability of the model, a column chart for prediction was created and calibration curves were used. Gene set enrichment analysis was used to evaluate pathway enrichment in patients with different risk cohorts. Finally, we investigated drug sensitivity between high-risk and low-risk cohorts.Results:We found that the survival rate of patients who received radiotherapy was significantly higher than that of patients who did not receive radiotherapy. In the constructed risk scoring model, high-risk patients have a worse prognosis. Pathway enrichment indicates that high-risk patients are enriched in regulating tumor cell growth, metabolism, and angiogenesis pathways, which may be a reason for poor prognosis in high-risk patients. High risk and low-risk patients have different sensitivities to different drugs. The 1, 3, and 5-year survival values predicted by the receiver operating characteristic curve were 0.82, 0.93, and 0.96, respectively, indicating the reliability of our prediction model. Finally, multiple regression analysis showed that the radiation therapy sensitive genes SSBP2, ELAVL3, and CST1 in the model can independently affect the prognosis of patients with uterine carcinosarcoma. Patients with high expression of SSBP2 have a better prognosis than those with low expression, while patients with high expression of ELAVL3 and CST1 have a poorer prognosis.Conclusion:We have developed a scoring method for uterine carcinosarcoma based on the effectiveness of radiotherapy. This method can evaluate the prognosis of patients with uterine carcinosarcoma and has certain guiding significance for the clinical treatment of subsequent uterine carcinosarcoma patients.

ObjectivesUterine carcinosarcoma is a rare, aggressive biphasic tumor comprising both carcinomatous and sarcomatous elements. The overall prognosis of women with uterine carcinosarcoma is poor, with a median overall survival of less than two years. The predictors of survival for patients with uterine carcinosarcoma in the Kingdom of Saudi Arabia have not yet been fully elucidated; this study therefore explored the demographic features and prognostic factors of uterine carcinosarcoma.MethodsThis A cross-sectional study was conducted among all confirmed carcinosarcoma cases at Princess Noorah Oncology Center, National Guard Hospital, Jeddah, Saudi Arabia, from January 2003 to December 2023. Data were collected on demographic features, medical history, stage, treatment modality, and disease outcome.ResultsA total of 34 patients with carcinosarcoma were identified, accounting for 4.7% of all endometrial cancer cases. Sixty percent of patients were diagnosed early, during stages 2B and below. The most common presentation was post-menopausal bleeding, occurring in 90% of the sample. Kaplan–Meir analysis revealed an overall median survival of 14 months.ConclusionThe findings confirmed the aggressiveness of the tumor. Late tumor stage was identified as a factor affecting patients’ survival and outcome, being associated with poor prognosis and short survival time.

Molecular comparison reveals distinct transcriptomic differences between uterine carcinosarcoma and papillary serous carcinoma distinguishable by DNA damage.

Improved overall survival with combined chemotherapy and radiation in stage I uterine carcinosarcoma: A National Cancer Database study

A molecular comparison reveals distinct transcriptomic differences between uterine carcinosarcoma and papillary serous carcinoma, distinguishable by DNA damage

In vitro and in vivo activity of datopotamab deruxtecan, an antibody-drug conjugate targeting trophoblast cell-surface antigen 2 (TROP2) in uterine and ovarian carcinosarcoma

Racial disparities in survival outcomes for uterine carcinosarcoma

Uterine carcinosarcoma (UCS) is an aggressive malignancy characterized by epithelial (C) and mesenchymal (S) components, with complex biology and poor treatment response. This study aims to enhance understanding of UCS through genomic, epigenomic, and transcriptomic analysis. Microdissected (C and S) tumor samples were processed for whole-genome sequencing (WGS), RNA-seqencing, and enzymatic methylation sequencing (EM-Seq). Multiplex immunohistochemistry (mIHC) and computational pathology techniques were employed to assess tumour microenvironment (TME). WGS and EM-seq of 18 samples from 9 patients revealed a low tumor mutation burden (TMB; median = 0.97 mutations/Mb) and no evidence of microsatellite instability (MSI). Driver mutations were identified in TP53 (94 %), PIK3CA (33 %), and PPP2R1A (22 %). Copy-number (CN) analysis revealed recurrent amplifications of MYC (67 %), PIK3CA (61 %), CCNE1 (56 %), AKT2 (44 %), and SMARCA4 (39 %). Comparative analysis of the C and S regions revealed no significant differences in mutation frequency, CN, transcriptomic and methylomic profiles. Both regions exhibited global hypomethylation, with functional enrichment for xenobiotic metabolism pathways in C and epithelial-to-mesenchymal transition pathways in S regions. Comparitive mIHC performed on 21 cases showed similar T cell and B cell densities, but a higher density of tumour-associated macrophages and PD-L1+ cells in the S component. Computational morphologic analysis showed substantial histomorphologic heterogeneity within and across UCS cases. By elucidating the complex interplay between the epithelial and mesenchymal components, this study enhances our understanding of UCS and informs the development of novel therapeutic strategies targeting both genomic alterations and the TME.