Carcinosarcoma Research Articles

Mutant PP2A Induces IGFBP2 Secretion to Promote Development of High-Grade Uterine Cancer.

Uterine serous carcinoma (USC) and uterine carcinosarcoma (UCS) tumors are uniquely aggressive, suggesting that the primary tumor is intrinsically equipped to disseminate and metastasize. Previous work identified mutational hotspots within PPP2R1A, which encodes the Aα scaffolding subunit of protein phosphatase 2A (PP2A), a heterotrimeric serine/threonine phosphatase. Two recurrent heterozygous PPP2R1A mutations, P179R and S256F, occur exclusively within high-grade subtypes of uterine cancer and can drive tumorigenesis and metastasis. Elucidation of the mechanisms by which PP2A-Aα mutants promote tumor development and progression could help identify therapeutic opportunities. Here, we showed that expression of these mutants in USC/UCS cell-lines enhanced tumor-initiating capacity, drove a hybrid epithelial-to-mesenchymal (EM) plasticity phenotype, and elevated secretion of the tumorigenic cytokine IGFBP2. Therapeutic targeting of the IGFBP2/IGF1R signaling axis using small molecules and genetic approaches resulted in marked tumor growth inhibition. Mechanistically, PP2A regulated IGFBP2 expression through the transcription factor, NF-κB, which harbors a B56 recognition motif. Collectively, these results identify a role for PP2A in regulating paracrine cancer cell signaling that can be targeted to block the initiation and metastasis of high-grade uterine cancer.

The Diverse Aspects of Uterine Serous Cancer: An NCI workshop on the status of and opportunities for advancement of research.

The marked increase in incidence and mortality in endometrial cancer over the last two decades is driven in part by rising rates of higher grade, more aggressive endometrial cancers with mutations in TP53, uterine serous cancers and their dedifferentiated component, uterine carcinosarcomas (collectively USC). USC rates have been increasing among all racial and ethnic groups, with higher rates of this aggressive uterine cancer in Black women. The National Cancer Institute (NCI) hosted a workshop in June 2023 to examine the diverse aspects of USC across epidemiology, biology, and molecular genetics, and to advance knowledge from basic to preclinical and translational efforts. Key stakeholders came together including basic scientists, clinical investigators, and patient advocates to identify critical research gaps that, when addressed, would facilitate more comprehensive and rapid progress in understanding and ultimately treating USC across all patients. NCI released a supplemental funding opportunity (NOT-CA-24-044) in Spring 2024 to facilitate rapid translation of these recommendations.

Platinum-free interval predicts overall survival in uterine carcinosarcomas

Platinum-free interval predicts overall survival in uterine carcinosarcomas

TROP2 as a novel target in uterine carcinosarcoma organoid models

TROP2 as a novel target in uterine carcinosarcoma organoid models

Survival outcomes according to molecular classification of uterine carcinosarcoma

Survival outcomes according to molecular classification of uterine carcinosarcoma

Development of a clinically relevant orthotopic uterine carcinosarcoma mouse model using patient-derived organoids

Development of a clinically relevant orthotopic uterine carcinosarcoma mouse model using patient-derived organoids

Uterine carcinosarcoma: Unraveling the role of epithelial-to-mesenchymal transition in progression and therapeutic potential.

Uterine carcinosarcoma (UCS) is a rare and highly aggressive gynecological malignancy characterized by poor prognosis. Due to its rarity, UCS remains relatively unexplored, and specific treatment guidelines are scarce. Despite standard treatments, including surgery, adjuvant chemotherapy, and radiotherapy, UCS has a high recurrence rate and poor overall prognosis. The aggressive nature of UCS is attributed to the metaplastic transformation of carcinomatous elements into sarcoma. This "biphasic" neoplasm features a mixture of epithelial and mesenchymal/tumor components, which partially share molecular signatures and exhibit a typical epithelial-to-mesenchymal transition (EMT) gene expression profile. Recent scientific advancements have highlighted the pivotal role of EMT in UCS progression and mortality. This review covers the epidemiology of UCS, theories regarding its origin, and the current state of clinical trials with more emphasis on the role of EMT drivers in UCS progression and scope of targeting these molecules. By shedding light on the molecular mechanisms supporting UCS, particularly emphasizing the importance of EMT, we aim to provide a more comprehensive understanding of the disease to support the development of more effective therapeutic strategies.

GSOR12 Presentation Time: 5:55 PM: Improved Survival with Adjuvant Radiation in Uterine Carcinosarcoma: A Retrospective Review

GSOR12 Presentation Time: 5:55 PM: Improved Survival with Adjuvant Radiation in Uterine Carcinosarcoma: A Retrospective Review

Metastatic Carcinosarcoma with a Sarcomatous Predominance?

Abstract Introduction/Objective Uterine carcinosarcoma (CS), also known as Malignant Mixed Müllerian Tumor, is a malignancy characterized by mixed epithelial and mesenchymal components. It is rare and aggressive, most frequently occurring in elderly, postmenopausal women with a median age of 65 years. CS has a tendency to metastasize with an overall poor prognosis. Fine needle aspiration can be useful in identifying metastatic disease, however, demonstration of both sarcomatous and carcinomatous components can be difficult. Methods/Case Report Our patient is a 68 year old female who was first diagnosed with endometrial carcinosarcoma on an endometrial biopsy in 2022. She subsequently underwent a total abdominal hysterectomy with radical dissection, bilateral salpingo-oophorectomy, upper vaginectomy, sentinel lymph node dissection as well as chemotherapy. Immunohistochemistry for MLH1, MSH2, MSH6 and PMS2 all showed intact nuclear expression. Remission was achieved for about a year, after which she was found to have a moderate right sided pleural effusion with right lower lung infiltrates. Also, a right upper lobe mass was reported on chest CT scan. Paracentesis was performed and cytology was consistent with predominantly atypical spindle cells accompanied by a mixed inflammatory infiltrate. Immunohistochemical stains were performed on the cell block, tumor cells were positive for smooth muscle actin, vimentin and negative for desmin, S-100, SOX-10, CD34, P63, TTF-1 and pancytokeratin. Cytology diagnosis was rendered as malignant cells present, consistent with metastatic CS. A subsequent lung mass core biopsy also confirmed the diagnosis. Results (if a Case Study enter NA) NA Conclusion The cytomorphological features in effusion samples from metastatic CS have the carcinomatous component readily identifiable, and only a minority of effusion samples show additional sarcomatous component. The exact diagnosis of CS may not be possible due to the absence of sarcomatous components. Alternatively, as we present in this rare case of metastatic CS, the sarcomatous component in the form of abundant atypical oval to spindle cells with hyperchromatic nuclei may be the only form of malignant cells present in the specimen. Careful morphological assessment of architectural patterns, a good past medical history, availability of cell blocks and immunohistochemistry are vital in providing an accurate diagnosis in such rare cases of metastatic CS.

Exploring Immunohistochemical Profiling in High-Grade Endometrial Stromal Sarcoma - A Case Study

Abstract Introduction/Objective High grade endometrial stromal sarcoma (HGESS) is a rare and aggressive tumor of endometrial stromal origin comprising about 0.2% of all uterine malignancies. It is often misdiagnosed preoperatively as uterine leiomyoma, leiomyosarcoma or endometrial carcinoma due to lack of well defined clinical and radiological features. We present an unusual case of HGESS with fibroid uterus and abnormal vaginal bleeding. Methods/Case Report A 73-year-old female with a past medical history of uterine fibroids presented with abnormal vaginal bleeding for 6 months. Her MRI uterus revealed enlarged uterus measuring 6.8 X 9.9 X 9.3 cm, multiple fibroids, and endometrial thickness of 4 mm. Hysteroscopic dilation and curettage revealed endometrial polyp and submucosal fibroid. Histopathology of submucosal fibroid revealed loosely cohesive tumor cells with high nuclear/cytoplasmic ratio, scant cytoplasm, and large prominent nucleoli, arranged in solid sheets with myxoid stroma. No glandular formation was identified. Tumor cell necrosis, bizarre tumor cells, and markedly increased mitotic activity, including atypical mitotic figures were present. Immunohistochemistry (IHC) revealed tumor cells diffusely positive for smooth muscle actin, CD10, p53, negative for AE1/AE3, CK7, cam5.2, EMA, ER, PR, desmin, and caldesmon. Ki-67 labels close to 50% of the tumor cells. Combined morphologic and IHC features favored the diagnosis of high-grade sarcoma, including leiomyosarcoma and HGESS. However, the possibility of carcinosarcoma (CS) could not be ruled out. Patient underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy. Final histopathological diagnosis revealed HGESS, pT1b. Lack of carcinomatous component and negative IHC staining for CK7, CAM 5.2, AE1/AE3 ruled out CS. IHC showed tumor cells diffusely positive for CD10, actin, desmin and CD 56, focally positive for caldesmon, cyclin D1 and CD 117 and negative for DOG 1, further supporting the diagnosis for HGESS over leiomyosarcoma. Results (if a Case Study enter NA) NA Conclusion Definitive diagnosis of HGESS is achieved through histology and IHC. An appropriate panel of IHC markers is essential to differentiate between endometrial stromal tumors from leiomyosarcoma and CS. Accurate diagnose of this rare clinical entity is critical especially in its initial stages owing to its poor prognosis and aggressive nature.

EBNA1BP2 identified as potential prognostic biomarker for multiple tumor types in pan-cancer analysis

BackgroundEpstein-Barr virus (EBV) infection has been closely linked to the development of various types of cancer. EB nuclear antigen 1 binding protein 2 (EBNA1BP2) is a crucial molecule for stable isolation of EBV in latent infection. However, the role of EBNA1BP2 in multiple tumor types is remains unclear. In this study, we comprehensively analyzed the functional characteristics of EBNA1BP2 and investigate its potential as a prognostic biomarker in pan-cancer.MethodsWe utilized data from TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus) databases and employed various bioinformatics analysis tools, including TIMER2.0, HPA, GEPIA2.0, PrognoScan, cBioPortal, CancerSEA, and BioGRID to explore the expression pattern, prognostic value, immune infiltration, and methylation level of EBNA1BP2 in pan-cancer. Additionally, we conducted enrichment analysis of genes associated with EBNA1BP2 to identify potential biological functions and pathways.ResultsOur analysis revealed that EBNA1BP2 expression was significantly higher in tumor tissues compared to tumor-adjacent tissues. We observed that lower expression of EBNA1BP2 in adrenocortical carcinoma (ACC), brain lower grade glioma (LGG), sarcoma (SARC), and uterine carcinosarcoma (UCS) was significantly associated with improved overall survival (OS) and disease-free survival (DFS). Furthermore, the promoter methylation level of EBNA1BP2 was downregulated in the majority of cancer types. At the single-cell level, EBNA1BP2 was found to be positively correlated with cell cycle and DNA repair processes, while negatively correlated with hypoxia. Additionally, EBNA1BP2 was associated with the infiltration of immune cells such as B cells, cancer-associated fibroblast cells, and CD8+ T cells. Gene enrichment analysis indicated that EBNA1BP2 was mainly involved in nucleoplasm and RNA binding pathways.ConclusionOur findings suggest that EBNA1BP2 may serve as a potential prognostic biomarker for survival in pan-cancer. Further experimental studies are needed to validate these findings and explore the underlying mechanisms by which EBNA1BP2 contributes to tumorigenesis.

Uterine carcinosarcomas: A case series of 9 cases from a low-income country.

Uterine carcinosarcomas (UCS) are rare aggressive biphasic tumors classified as a subtype of high-grade uterine carcinomas. However, these tumors have particular histopathological features and clinical behavior with worse prognosis than high-grade uterine carcinomas. The incidence of UCS is increasing and more studies are required to elucidate their clinical and histopathological characteristics. Herein, we report clinicopathological features of 9 cases of UCS in a low-income country. We retrospectively collected all cases of UCS at our Pathology Department over a period of 4 years. The diagnosis was performed on formalin-fixed, paraffin-embedded and hematoxylin and eosin-stained surgical specimens. Nine surgically treated cases of UCS have been registered, representing 12.67% of all uterine malignancies with a mean age of 58.88 years (range: 50-65 years). Abdominal pain and metrorrhagia were the main clinical presentations. The epithelial component of UCS was often a serous carcinoma (66.66%) and patients presented with large tumors (mean size of 9.24 cm, range of 5-19 cm), with advanced FIGO stages (stages III-IV) in 5/9 patients (55.55%). Follow-up data were available in 5/9 patients among which only 2 were alive 2 and 25 months after the surgical treatment (overall survival of 40%). UCS are rare and aggressive uterine tumors with very poor prognosis especially in low-income countries.

Study on the expression and prognostic relationship of MYL6B in liver cancer based on bioinformatics.

Primary liver cancer is a prevalent and deadly cancer type. Despite treatment advances, prognosis remains poor, with high recurrence rates. Early detection is crucial but challenging due to the disease's insidious nature. Myosin proteins play significant roles in cancer development, influencing cell migration, invasion, and tumor suppression. MYL6B, a myosin light chain, is involved in various cellular processes and has been associated with poor prognosis in colorectal adenocarcinoma and potential as a biomarker in breast cancer. To investigate the expression of MYL6B in liver hepatocellular carcinoma (LIHC) and its impact on prognosis and potential mechanisms of action using bioinformatics methods. The expression of MYL6B in pan-cancer and normal tissues was analyzed using the gene expression profiling interactive analysis 2 and tumor immune estimation resource databases. The expression level of MYL6B in LIHC tissues and its relationship with prognosis were analyzed, immunohistochemical analysis of MYL6B and its effect on immune cell infiltration, and the protein network were further studied. MYL6B was highly expressed in diffuse large b-cell lymphoma, LIHC, pancreatic adenocarcinoma, skin cutaneous melanoma, thymoma, uterine corpus endometrial carcinoma, uterine carcinosarcoma, and lowly expressed in kidney chromophobe, acute myeloid leukemia, testicular germ cell tumors. The expression level of MYL6B was significantly different between cancer and normal tissues. It had a significant impact on both overall survival and disease-free survival. MYL6B is highly expressed in hepatocellular carcinoma and its expression level increases with cancer progression. High MYL6B expression is associated with poor prognosis in terms of overall survival and recurrence-free survival. The immunohistochemical level of MYL6B is high in hepatocellular carcinoma tissues, and MYL6B has a high level of immune infiltration inflammation. In protein network analysis, MYL6B is correlated with MYL2, MYL6, MYL9, MYLK4, MYLK2, MYL12A, MYL12B, MYH11, MYH9 and MYH10. The expression level of MYL6B in LIHC was significantly higher than in normal liver tissues, and it was correlated with the degree of differentiation survival rate, and immune infiltration. MYL6B is a potential target for LIHC treatment.

P53 Immunohistochemistry staining patterns and prognosis significance in 212 cases of non-endometrioid endometrial cancer

ObjectiveTo investigate the immunohistochemistry (IHC) staining pattern and prognostic significance of p53 in non-endometrioid endometrial cancer (non-EEC). MethodsThis study retrospectively included 212 non-EEC patients, with histological types including serous carcinoma (SC), clear cell carcinoma (CCC), mixed carcinoma (MC), undifferentiated carcinoma (UC), and carcinosarcoma (CS). p53 IHC was interpreted as normal/wild-type and abnormal/mutant-type, the latter including overexpression, complete absence, and cytoplasmic staining patterns. Moreover, uncommon p53 subclonal/heterogeneous staining patterns were described. Disease-free survival (DFS) and overall survival (OS) were employed as endpoints to evaluate the prognostic significance of p53. ResultsIn 212 non-EEC cases, 50 (23.6 %) were p53 wild-type, while 162 (76.4 %) displayed abnormal p53 staining. Overexpression was the predominant abnormal p53 staining pattern (122/162), complete absence followed (33/162). All SCs exhibited the mutant p53 staining pattern. The p53 abnormal expression rates in CCC, MC, UC, and CS were 37.5 %, 78.9 %, 35.7 %, and 75.7 %, respectively. Interestingly, of the 12 MC cases with SC components, barring one with p53 subclonal staining, all showed the mutant-type staining. The concordance rate for p53 expression between epithelial and mesenchymal components of CS was 94.3 % (66/70). Kaplan-Meier curves indicated patients with p53 abnormalities had worse DFS compared to those with wild-type p53 (P=0.025). Multivariate Cox regression confirmed that p53 (HR: 2.270, 95 % CI: 1.124–4.586, P=0.022) independently predicted DFS in non-EEC patients, though not for OS. ConclusionsNon-EEC patients with various histological types exhibit different p53 staining patterns. However, abnormal p53 expression, regardless of histological type, implies a poor DFS in non-EEC patients.

Uterine carcinosarcoma with heterologous chondrosarcomatous differentiation and bone formation – A rare case report

Uterine carcinosarcoma with heterologous chondrosarcomatous differentiation and bone formation – A rare case report

Clinical and Morphological Aspects of Aggressive Salivary Gland Mixed Tumors: A Narrative Review.

Salivary gland tumors are a rare and heterogeneous group of neoplasms of the head and neck region. The mixed category of these tumors include the following entities: pleomorphic adenoma (PA), carcinoma ex pleomorphic adenoma (CEPA), salivary carcinosarcoma (CS), and metastasizing PA (MPA). The most common benign tumor of the salivary glands is PA. Metastasis and malignant degeneration have been reported in cases of PA of a salivary gland origin. Judging by their behavior, MPA, CEPA, and CS can be considered aggressive tumors. Invasive CEPA has been identified in the parotid gland more frequently. MPA and CS cases reported in the current literature are rare. In this paper, we present, narratively, the clinico-morphological features of this group of mixed tumors.

Uterine Carcinosarcoma: Outcome of Management of Eight Cases

Uterine Carcinosarcoma: Outcome of Management of Eight Cases

Pan-Cancer Analysis Reveals Long Non-coding RNA (lncRNA) Embryonic Stem Cell-Related Gene (ESRG) as a Promising Diagnostic and Prognostic Biomarker.

Embryonic stem cell-related gene (ESRG; also known as HESRG) is a long non-coding RNA (lncRNA). It is involved in the regulation of human pluripotent stem cells (hPSCs) self-renewal. ESRG gene has the ability to interact with chromatins, different RNA types, and RNA binding proteins (RBP); thus making ESRG be considered an oncogenic lncRNA, where its expression is detected in various tumor tissues. This study aimed to evaluate the prospective diagnostic and prognostic values of ESRG in various human cancers. The expression of ESRG in various cancers was analyzed using the Gene Expression Profiling Interactive Analysis (GEPIA), Tumor Immune Estimation Resource (TIMER), and University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN) databases. Moreover, the correlation between the expression of ESRG and clinical pathological parameters was analyzed using UALCAN. The effect of ESRG expression on the survival outcome was evaluated using Kaplan-Meier plotter, UALCAN, GEPIA, and TIMER. The correlation between ESRG expression and immune cell infiltration was studied by TIMER. Additionally, the genetic alterations were investigated cBioportal. Our findings were validated using the GEO2R database. Our results showed ESRG to be significantly up-regulated incolon adenocarcinoma (COAD) and lung squamous cell carcinoma (LUSC) with p<0.001, in addition to rectum adenocarcinoma (READ), and uterine carcinosarcoma (UCEC) withp<0.01. Regarding pathogenic stages, there was a significant upregulation in stages 2, 3, and 4 compared to normal in COAD and stages 1, 2, and 3 for LUSC patients. The combined prognostic analysis showed that the up-regulated expression of ESRG was associated with better survival outcomes in patients with brain lower-grade glioma (LGG). Our results demonstrate a significant negative correlation between ESRG expression and the abundance of CD8+T cells in COAD, READ, LUSC, and UCEC. Additionally, ESRG was mutated in 0.77 (<1%) of the queried samples, and the most prevalent ESRG mutations are deep deletion mutations, followed by amplification. Analysis of ESRG across various cancer types elucidated its potential to be used as a diagnostic biomarker in COAD, LUSC, READ, and UCEC and a promising prognostic biomarker in LGG. Our findings provide useful insights for future research.

Prognostic Nomogram for Predicting Survival, Clinicopathological Analysis, and Racial Disparities in Uterine Carcinosarcoma: A Retrospective Population-Based Study

Introduction: Uterine carcinosarcoma is an aggressive gynecologic malignancy that accounts for 5% of all gynecological malignancies. There is a disproportion in its incidence and mortality among different races. This study describes demographic and clinicopathological factors and racial disparities affecting the survival of patients with uterine carcinosarcoma. Methods: Data on uterine carcinosarcoma patients were obtained from the Surveillance, Epidemiology, and End Results (SEER) database from 2000 to 2020. Results: Of the 11,338 patients identified, the median age at diagnosis was 68 years, and the five-year cause-specific survival (CSS) rate was 38.7%. for all races. Compared with Asian patients (39.5%, 95% CI, 36.0–43.4%), Hispanic patients (39.4%, 95% CI, 36.5–42.5%), and White patients (37.9%, 95% CI, 36.7–39.2%), Black patients accounted for 21% of the patients and had a significantly lower 5-year CSS (95% CI, 27.2–31.2%). The CSS rates were 84.4% (95% CI, 83.3–85.6%) for localized tumors, 68.5% (95% CI, 66.9–70.1%) for regional tumors, and 39.0% (95% CI, 36.9–41.2%) for distant tumors. Multimodal treatment involving chemotherapy, surgery, and radiation improved the overall one- and five-year survival rates by 88.2% (95% CI, 87.0–89.5%) and 52.8% (95% CI, 50.7–55.1%), respectively, across all disease stages. Multivariate analysis identified age &gt;60 years, Black race, tumor size &gt;4 cm, and distant metastases as independent risk factors for mortality (p &lt; 0.0001). Conclusions: This large database study presents the most up-to-date epidemiological information regarding cases of uterine carcinosarcoma. The findings suggest that a combination of surgery, chemotherapy, and radiation may be most efficacious in treating this malignancy, especially in patients with distant disease.

Utilizing a high power light-emitting diode to induce apoptosis of uterine carcinosarcoma (malignant mixed mullerian tumor) cells through a bi-phasic effect

Utilizing a high power light-emitting diode to induce apoptosis of uterine carcinosarcoma (malignant mixed mullerian tumor) cells through a bi-phasic effect