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Ovarian carcinosarcoma in hereditary breast and ovarian cancer syndrome is rare. A 43‐year‐old woman with a family history of prostate and uterine or ovarian cancer had an 8‐cm mass in the right ovary. Although computed tomography suggested peritoneal dissemination to the Douglas pouch, she wanted to preserve her fertility; therefore, she underwent a right salpingo‐oophorectomy. Histopathological diagnosis was carcinosarcoma consisting of high‐grade serous carcinoma and sarcomatous components, including cartilage. Three weeks later, she underwent radical surgery. The disease was classified as advanced stage IIIB (FIGO 2014). A germline BRCA2 pathogenic variant was identified. After postoperative adjuvant chemotherapy, maintenance therapy with a poly(adenosine diphosphate‐ribose) polymerase (PARP) inhibitor was continued for 25 months without recurrence. A detailed examination of a mass in her left breast at her first visit revealed a ductal carcinoma in situ. PARP inhibitors may be effective as maintenance therapy for advanced ovarian carcinosarcoma with germline BRCA mutations. [ABSTRACT FROM AUTHOR]

Objectives: Ovarian carcinosarcoma (OCS) is a rare and lethal type of ovarian cancer. Despite its incredibly poor prognosis, it has received little research attention. In this study, we aim to evaluate the molecular features of OCS and elucidate their clinical significance. Study methods: We examined 30 OCS by immunohistochemistry (IHC) and targeted panel sequencing collected from a single institution (2003–2013) as the initial molecularly characterized cohort (Cohort A). From November 2016 to April 2023, we collected an additional 67 OCS cases from three institutions across British Columbia and Alberta as the contemporary cohort (Cohort B) for clinical correlation. The Kaplan–Meier method was used to estimate overall and progression-free survival, and differences in survival rates were compared using the log-rank test. All tests were two-sided. A p-value of less than 0.05 was considered statistically significant. Results: The majority of OCS (82%) in the initial Cohort A were p53-mutated, and the carcinomatous component displayed the histological and molecular features of a high-grade tubo-ovarian serous carcinoma (HGSC-like). In a minority of OCS, the epithelial components were characteristics of endometrioid or clear cell carcinomas, and IHC staining was wild type for p53. In the contemporary Cohort B, we observed the same histological findings related to the p53 IHC staining pattern. The median overall survival of the p53-mutated HGSC-like OCS (47 patients) was significantly higher (43.5 months) compared with that of the p53 wild-type OCS (10 patients, 8.8 months; P < 0.01). Pathogenic BRCA1/2 germline/ somatic mutations were observed in 7 patients (17.5%) of HGSC-like OCS, and all these patients were alive at 3 years from diagnosis compared to a 51% 3-year survival among the patients with BRCA1/2 wild-type HGSC-like OCS (33 patients) (p = 0.022). Majority of patients (6/7) with BRCA1/2-mutated OCS received poly (ADP-ribose) polymerase inhibitor as maintenance therapy in this cohort. Conclusions: Most OCSs have a morphologic and molecular profile resembling HGSC; however, some OCSs display a molecular profile that suggests origin through non-serous oncogenic pathways. This molecular distinction has both prognostic and treatment (predictive) implications. These findings underscore the importance of routine p53 IHC testing on all OCS and BRCA1/2 testing on p53-mutated OCS. [ABSTRACT FROM AUTHOR]

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Purpose: To clarify the diagnostic utility and formation of the Mille-feuille sign for ovarian carcinosarcoma (OCS) on MRI, and to evaluate the other MRI findings and serum markers compared to ovarian metastases from colorectal carcinoma (OMCRC). Method: Three blinded radiologists retrospectively reviewed MR images of 12 patients with OCS, 18 with OMCRC, and 40 with primary ovarian carcinoma (POC) identified by the electronic database of radiology reports. The interobserver agreement was analyzed using Fleiss' kappa test. Their MRI characteristics and tumor markers were compared using Fisher's exact test and Mann–Whitney's U test. Receiver operating characteristic curve analyses were used to determine the cutoff points for the ADC value. This study was approved by the institutional ethics committee. Results: Interobserver agreement analysis was moderate or higher for all MRI characteristics. The frequency of Mille-feuille sign was comparable for both OCS and OMCRC groups, and predominantly higher than that of the POC group (p < 0.001, p < 0.001), respectively. Pathologically, the Mille-feuille sign in OCS reflected alternating layers of tumor cells with stroma and necrosis or intraluminal necrotic debris. Compared to OMCRC, intratumoral hemorrhage (p = 0.02), margin irregularity (p = 0.048), unilateral adnexal mass (p = 0.02), and low ADC values (p < 0.01) were more frequently observed and serum CEA levels was significantly lower (p = 0.007) in the OCS group. Under setting of the cutoff value of ADC at 0.871 × 10−3mm2/s, the discriminative ability for OCS showed 66.7% sensitivity, 94.4% specificity, and 81.0% accuracy, respectively. Conclusions: The Mille-feuille sign was seen in both OCS and OMCRC. MR findings of intratumoral hemorrhage, margin irregularity, unilateral adnexal mass, low ADC values, and low serum CEA levels can be useful in differentiating OCS from OMCRC. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to evaluate mesothelin (MSLN) expression and determine its clinical significance and correlation with human epidermal growth factor receptor 2 (HER2) expression in gynecological carcinosarcoma. Methods: We retrospectively evaluated patients with uterine carcinosarcoma (UCS) and ovarian carcinosarcoma (OCS) who underwent surgery between 1997 and 2019. Immunohistochemical staining of formalin-fixed, paraffin-embedded specimens for MSLN (clone SP74) and HER2 (clone 4A5) was also performed. MSLN was scored using the H-score and 4-tired scoring system (0-3+). MSLN positivity was defined as any positive cell at any intensity, while high MSLN expression was defined as an intensity of =2+ in =30% of tumor cells. HER2 expression was scored according to modified 2018 American Society of Clinical Oncology/College of American Pathologists criteria. Results: A total of 128 patients were recruited, including 119 with UCS and 9 with OCS. All cases in UCS exhibited MSLN positivity, and 33.9% showed high-MSLN expression. Clinicopathological characteristics were not significantly associated with high or low-MSLN expression. However, the high-MSLN group showed more prolonged overall survival (OS) than the low-MSLN group (not assessed vs. 36.8 months; hazard ratio=0.48, 95% confidence interval=0.26-0.89, p=0.016). HER2-high patients had higher MSLN expression than HER2- negative patients. In high-MSLN and low-MSLN expression groups, HER2 status did not affect OS. OCS showed 100% MSLN positivity, with 66.6% high-MSLN. Conclusion: MSLN expression is widely observed in gynecological carcinosarcomas. Moreover, high-MSLN expression is a favorable prognostic factor for UCS. MSLN could be a promising therapeutic target for UCS, even in the era of anti-HER2 therapy. [ABSTRACT FROM AUTHOR]

ObjectivesOvarian carcinosarcoma (OCS) is a rare and lethal type of ovarian cancer. Despite its incredibly poor prognosis, it has received little research attention. In this study, we aim to evaluate the molecular features of OCS and elucidate their clinical significance.Study methodsWe examined 30 OCS by immunohistochemistry (IHC) and targeted panel sequencing collected from a single institution (2003–2013) as the initial molecularly characterized cohort (Cohort A). From November 2016 to April 2023, we collected an additional 67 OCS cases from three institutions across British Columbia and Alberta as the contemporary cohort (Cohort B) for clinical correlation. The Kaplan–Meier method was used to estimate overall and progression-free survival, and differences in survival rates were compared using the log-rank test. All tests were two-sided. A p-value of less than 0.05 was considered statistically significant.ResultsThe majority of OCS (82%) in the initial Cohort A were p53-mutated, and the carcinomatous component displayed the histological and molecular features of a high-grade tubo-ovarian serous carcinoma (HGSC-like). In a minority of OCS, the epithelial components were characteristics of endometrioid or clear cell carcinomas, and IHC staining was wild type for p53. In the contemporary Cohort B, we observed the same histological findings related to the p53 IHC staining pattern. The median overall survival of the p53-mutated HGSC-like OCS (47 patients) was significantly higher (43.5 months) compared with that of the p53 wild-type OCS (10 patients, 8.8 months; P < 0.01). Pathogenic BRCA1/2 germline/somatic mutations were observed in 7 patients (17.5%) of HGSC-like OCS, and all these patients were alive at 3 years from diagnosis compared to a 51% 3-year survival among the patients with BRCA1/2 wild-type HGSC-like OCS (33 patients) (p = 0.022). Majority of patients (6/7) with BRCA1/2-mutated OCS received poly (ADP-ribose) polymerase inhibitor as maintenance therapy in this cohort.ConclusionsMost OCSs have a morphologic and molecular profile resembling HGSC; however, some OCSs display a molecular profile that suggests origin through non-serous oncogenic pathways. This molecular distinction has both prognostic and treatment (predictive) implications. These findings underscore the importance of routine p53 IHC testing on all OCS and BRCA1/2 testing on p53-mutated OCS.

Opinion statement: Ovarian carcinosarcoma (OCS), also known as a malignant mixed Müllerian tumour (MMMT), is a rare and aggressive form of cancer that accounts for less than 5% of ovarian cancers. It is characterized by high morbidity and mortality rates, with a median overall survival (OS) of less than 2 years. Several factors, including advancing age, nulliparity, reduced lactation rates, decreased use of oral contraceptive pills, genetic mutations in BRCA (breast cancer) genes, and the use of assisted reproductive technology, may increase the risk of OCS. Poor prognostic factors include an advanced stage at diagnosis, older age, lymph node metastasis, suboptimal surgical cytoreduction, the presence of heterologous features on histopathology, and increased expression of vascular endothelial growth factor (VEGF), tumour protein p53, and p53 alongside Wilms tumour 1 (WT1). The main treatment approach for OCS is cytoreductive surgery followed by platinum-based chemotherapy, although immunotherapy is showing promise. Homologous recombination deficiency (HRD) testing may enhance outcomes by enabling personalized immunotherapy and targeted therapies for specific patient groups, thereby reducing unnecessary side effects and healthcare costs. However, there is currently a lack of standardised treatment regimens for OCS patients, with most studies consisting of case reports and a shortage of suitable comparator groups. This article aims to provide clinicians with information on the epidemiology, risk factors, prognostic factors, and latest therapeutic advancements in OCS. [ABSTRACT FROM AUTHOR]

We report a case of rare and aggressive ovarian carcinosarcoma with a germline pathogenic BRCA2 variant. A patient with a history of breast cancer who developed an inflammatory ovarian tumor with peritonitis carcinomatosis involving the appendix suffered from cachexia. Following three cycles of weekly paclitaxel and carboplatin chemotherapy, emergency surgery was required owing to sepsis. Bilateral salpingo‐oophorectomy, total hysterectomy, appendectomy, and small intestine adhesiolysis were performed. Histologically, the tumor comprised an admixture of carcinomatous and sarcomatous components, with involvement of the appendix, which had caused perforation and abscess formation. The final diagnosis was ovarian carcinosarcoma with a germline pathogenic BRCA2 variant, c.658_659del (p.Val220fs). The patient responded completely to adjuvant chemotherapy. A combination of chemotherapy and surgery might be beneficial to patients with ovarian carcinosarcoma and germline pathogenic BRCA2 variants with a poor general condition. This is the first report of ovarian carcinosarcoma with a germline pathogenic BRCA2 variant that responded favorably to chemotherapy. [ABSTRACT FROM AUTHOR]

Objective: Female genital system carcinosarcomas are rare gynecologic diseases that most commonly involve the corpus uteri. This study aimed to investigate the differences between uterine and ovarian carcinosarcomas in terms of histological, clinicopathological, and survival characteristics and evaluate the adjuvant treatment options received by patients, particularly at the sites of the first relapse. Material and Method: This retrospective study was conducted on patients with the diagnosis of uterine carcinosarcomas and ovarian carcinosarcomas treated between January 1, 2006, and December 31, 2020. Records of 54 patients (42 patients with uterine carcinosarcoma and 12 patients with ovarian carcinosarcoma) who underwent debulking surgery were analyzed. Results: No difference was found in terms of mean tumor diameter, lymphovascular space invasion, lymph node involvement, and omental assessment. Recurrence occurred in 18 patients with uterine carcinosarcoma and eight patients with ovarian carcinosarcoma. Distant organ metastases such as lung or brain were not detected in any of the patients during the follow-ups. Kaplan-Meier analysis showed that disease-free survival (DFS) and overall survival (OS) in the uterine carcinosarcoma and ovarian carcinosarcoma groups were similar (p=0 .938 for OS and p=0.328 for DFS). Conclusion: Ovarian carcinosarcomas can be seen at an earlier age than uterine carcinosarcomas, and it has fewer signs that may indicate disease. It should be underlined that 41.7% of patients with ovarian carcinosarcoma were in the premenopausal period. [ABSTRACT FROM AUTHOR]

Folate receptor alpha (FRα), which is expressed in various cancers, is a potential therapeutic target. However, its expression and clinical significance in uterine (UCS) and ovarian carcinosarcoma (OCS) remain to be elucidated. This retrospective study included patients with gynecologic carcinosarcoma who underwent primary surgery between 1997 and 2019 at our institution. Immunohistochemical staining of surgical FFPE specimens was performed for FRα and HER2. FRα was evaluated using the H-score and the 4-tired scoring system (0 to 3+). Subsequently, FRα expression (≥5% of tumor cells with ≥1+ intensity) and FRα-high (score 2+ and 3+) were evaluated. HER2 was scored according to the modified ASCO/CAP criteria. The association between FRα-high and clinicopathological features, HER2 expression, and survival was assessed in UCS. A total of 120 patients with UCS and nine patients with OCS were included. In UCS, FRα expression was observed in all patients, whereas FRα-high status was present in 20% of patients. Among HER2-negative UCS, 34% exhibited FRα-high. No significant association was observed between clinicopathological characteristics and FRα status. During the follow-up period (median 34.5 mo), FRα-high was not strongly associated with progression, free survival, and overall survival. All the OCS tumor specimens showed FRα-high expression. FRα expression was observed in all the UCS and OCS specimens, including HER2-negative UCS patients. This widespread FRα expression suggests that FRα-targeted therapies may hold promise for the treatment for gynecologic carcinosarcoma. However, in uterine carcinosarcoma, no significant relationship was observed between FRα expression and clinicopathological features or prognosis. • FRα is widely expressed in gynecologic carcinosarcomas. • FRα-high expression was detected in 34% of HER2-negative uterine carcinosarcomas. • FRα-high expression had no prognostic impact on patients with uterine carcinosarcoma. [ABSTRACT FROM AUTHOR]

Ovarian carcinosarcoma (OCS) is an uncommon and aggressive malignancy, with poor response to current treatment approaches and no clear guidelines. Our aim is to evaluate the outcomes of an OCS cohort after cytoreduction with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). A descriptive cohort study was performed. Patients who underwent CRS/HIPEC for peritoneal dissemination from tubo-ovarian malignancies (1999–2021) were retrospectively reviewed. Patients with confirmed histopathologic diagnosis of FIGO stage III/IV OCS were included. Overall (OS) and progression-free survival (PFS) were determined with the Kaplan-Meier method. Of 267 patients with tubo-ovarian malignancies reviewed, 7.5% (20/267) had OCS. Of these, 16 underwent CRS/HIPEC, including 9 for a new diagnosis and 7 for disease recurrence. Median age at surgery was 66.5 (IQR: 54.5–74.5) years. Nine (56.2%) patients were FIGO stage IV. Median peritoneal cancer index was 22 (IQR: 14–28). Complete cytoreduction was achieved in 15/16 (93.7%) cases. HIPEC agents included carboplatin (n = 7), cisplatin+doxorubicin (n = 4), and melphalan (n = 5). Major complications occurred in 4/16 (25%), with no 90-day mortality. Median follow-up was 41.8 months. Median PFS was 11.7 (95%CI: 10.5–17.1) months. Malignant bowel obstruction occurred in 3/16 (18.7%). Median OS from CRS/HIPEC was 21.3 (95%CI: 16.3–31.6) months, not reached for newly diagnosed vs 19.7 months for recurrent patients (p = 0.23). CRS/HIPEC showed promising survival and abdominal disease control with low rates of malignant obstruction in patients with advanced stage OCS. Collaborative studies with larger cohorts and longer follow-up may further elucidate the role of CRS/HIPEC in OCS. [ABSTRACT FROM AUTHOR]

To describe the prevalence of germline pathogenic variants (gPVs) in endometrial and ovarian carcinosarcomas and determine if gPVs are drivers of carcinosarcoma. Patients with endometrial or ovarian carcinosarcomas who underwent clinical tumor-normal sequencing from 1/1/2015 to 6/1/2021 and consented to germline assessment of ≥76 cancer predisposition genes were included. In patients with gPVs, biallelic inactivation was identified through analysis of loss of heterozygosity and somatic pathogenic alterations. Of 216 patients identified, 167 (77%) were diagnosed with endometrial carcinosarcoma and 49 (23%) with ovarian carcinosarcoma. Overall, 33 gPVs were observed in 29 patients (13%); 20 gPVs (61%) had biallelic loss in tumors. The rate of high-penetrance gPVs overall was 7% (16 of 216); 88% of high-penetrance gPVs had biallelic loss. In the endometrial carcinosarcoma cohort, 22 gPVs were found in 19 (11%) of 167 patients; 12 gPVs (55%) had biallelic loss in tumors, including 8 (89%) of 9 in high-penetrance gPVs. Among the ovarian carcinosarcoma cohort, 11 gPVs were found in 10 (20%) of 49 patients; 8 gPVs (73%) had biallelic loss in tumors, and all evaluable high-penetrance gPVs (n = 6) had biallelic loss. All gPVs in homologous recombination (BRCA1 , BRCA2 , RAD51C) and Lynch syndrome (MSH2 , MSH6) genes had biallelic loss in tumors (n = 15). gPVs in genes affecting homologous recombination- or Lynch-associated mismatch repair exhibited biallelic inactivation within tumors, suggesting likely drivers of gynecologic carcinosarcoma. Our data support germline testing for patients with gynecologic carcinosarcomas, given implications for treatment and risk-reduction in patients and at-risk family members. • In this cohort of patients with gynecologic carcinosarcomas, 13% had a germline pathogenic variant (gPV). • In endometrial carcinosarcoma, 8 (89%) of 9 gPVs in high-penetrance genes exhibited biallelic inactivation. • In ovarian carcinosarcoma, all 6 gPVs in high-penetrance genes exhibited biallelic inactivation. • All gPVs in homologous recombination and Lynch syndrome-related genes had biallelic loss in tumors. • Germline testing of patients with gynecologic carcinosarcomas is important, as some gPVs drive carcinosarcoma development. [ABSTRACT FROM AUTHOR]

Introduction. Despite that ovarian carcinosarcoma (OCS) is an extremely rare disease, it is of great medical and social importance by taking into account very high level of overall mortality, recurrence, metastasis, and economic costs.Aim: to summarize current data on various aspects of OCS.Materials and Methods. The search strategy for English written papers published in databases PubMed/MEDLINE, Scopus, Web of Science, Google Scholar was based on the following keyword queries: «ovarian carcinosarcoma», «etiology and pathogenesis», «epidemiology», «classification», «clinical picture», «diagnosis», «treatment». The search depth was limited within the years 2010–2022, by prioritizing the search depth within the last 5 years (2017–2022).Results. We found 48 articles in English, published from 2016 to 2022, of which 47 (97.9 %) articles were published within the last 5 years. Scientific data are represented by studies with a small patient sample and with low evidence base. The results of the analysis for identified publications showed a limited, fragmented and inconsistent scientific data both in terms of etiology, pathogenesis and treatment, as well as an impact of OCS stages, age and other risk factors on the likelihood of relapses.Conclusion. The lack of extensive clinical studies along with observed substantial number of controversial issues may be accounted for by OCS low prevalence and complex pathogenesis. Nevertheless, the results obtained during the generalization of scientific knowledge provide a realistic insight into the current state of global science about this medical and social disease and may be used to improve the diagnostics and treatment of OCS patients.

Abstract Skin metastasis of ovarian cancer is extremely rare. We report an unusual case of ovarian carcinosarcoma with cutaneous metastasis of carcinomatous component that displayed distinct clinical manifestation. A 48-year-old woman presented to the dermatologist complaining of a new onset of erythematous, plaque-like skin rash with multiple small nodules on the left inner thigh, the area measuring 8 × 5cm. While the patient had no history of dermatologic conditions, she underwent a total hysterectomy and bilateral salpingo-oophorectomy, omentectomy, and lymph node dissection 16 months ago with a pathology confirmed stage IIIC ovarian carcinosarcoma. Of note, the carcinomatous component, mainly adenocarcinoma with hybrid features of seromucinous, endometrioid and minor high-grade serous carcinoma, involved bilateral fallopian tubes, omentum, and parametrium with extensive lymph node metastases. A skin biopsy specimen revealed an adenocarcinoma involving epidermis, dermis, and subcutaneous tissue with nodular contours, consistent with metastatic carcinomatous component of carcinosarcoma. Both carcinomatous component of primary ovarian carcinosarcoma and metastatic adenocarcinoma in the skin demonstrated Pax8, WT-1, and ER positivity and a mutation pattern of p53. The patient passed away 15 months after identification of skin metastasis. This case represents a unique example of cutaneous metastasis of ovarian carcinosarcoma with distinct clinical manifestation and detailed histopathological description. Alertness to the possibility of cutaneous metastasis, in combination with clinical history, morphological and immunohistochemical findings, is critical for a definitive classification.

Carcinosarcomas are highly aggressive gynecologic malignancies containing both carcinomatous and sarcomatous elements with heterogeneous HER2/neu expression and limited therapeutic options. We compared the efficacy of trastuzumab deruxtecan (DS-8201a), a novel HER2/neu-targeting antibody-drug conjugate (ADC) to an ADC isotype control (MAAA-9199) against primary uterine and ovarian carcinosarcomas in vitro and in vivo. Twelve primary carcinosarcoma (CS) cell lines were evaluated for HER2/neu surface expression by immunohistochemistry (IHC) and by flow cytometry, and gene amplification by fluorescence in situ hybridization (FISH) assays. The in vitro experiments included cytotoxicity and bystander killing effect assays on three cell lines of variable HER2/neu expression. In vivo activity was studied in a mouse CS xenograft model of 3+ HER2/neu uterine CS. In vitro studies showed that DS-8201a was highly effective against uterine and ovarian CS cell lines demonstrating 3+ HER2/neu expression compared to MAAA-9199 control; there was no significant improvement in the 0 HER2/neu CS cell line. However, DS-8201a induced efficient bystander killing of 0 HER2/neu tumor cells when admixed with 3+ HER2/neu cells. In vivo studies confirmed that DS-8201a was more effective than MAAA-9199 in 3+ HER2/neu-expressing CS xenografts. DS-8201a may represent a novel and highly effective ADC against HER2/neu-expressing CS. • DS-8201a exhibited marked cytotoxicity in vitro among HER2/neu expressing cell lines. • 0 HER2/neu cells are receptive to bystander killing effect from DS-8201a when mixed with 3+ HER2/neu-expressing cells. • DS-8201a inhibits HER2/neu expressing carcinosarcoma tumor growth in patient-derived xenografts. • DS-8201a is an effective antibody drug conjugate against HER2/neu-expressing uterine and ovarian carcinosarcomas. [ABSTRACT FROM AUTHOR]

This open-label phase II clinical trial evaluated the antitumor activity and safety of trabectedin in patients with advanced ovarian (OC) or uterine carcinosarcomas (UC). Eligible patients were adults (≥18 years) with histologically proven recurrent OC/UC not amenable to surgery or radiotherapy who received up to two prior chemotherapy lines. Trabectedin 1.3 mg/m2 was administered as a 3-h infusion every three weeks. The primary endpoint was objective response rate (ORR) as per RECIST v.1.1. If at least 8 of 43 patients (18.6%) achieve an objective response, trabectedin would be declared worthy for further investigations. Forty-five patients with either OC (n = 32) or UC (n = 13) from seven MITO centers across Italy were enrolled. The ORR was 11.9% (90% CI: 6–23) and included two patients with a complete response and three with a partial response. Eight patients (19.0%) had disease stabilization for a disease control rate of 31.0% (90% CI: 20–44). Median progression-free survival was 2.01 months (95% CI: 1.78–2.30) and median overall survival was 4.64 months (95% CI: 3.19–8.29). Neutrophil count decreases (n = 8, 18.2%) and transaminase increases (n = 6, 13.6%) were the most common grade 3–5 adverse events related with trabectedin. Two patients died due to trabectedin-related grade 5 hematological toxicity. Although trabectedin did not meet the prespecified activity criteria, it confers modest but clinically meaningful benefit to patients with advanced OC/UC as being as effective as any other available treatment for this indication. The toxicity profile appears in line with that previously reported for the drug. • Trabectedin did not meet the prespecified activity criteria to be considered worthy for further investigations in OC or UC. • Yet, in heavily pre-treated patients trabectedin elicited modest clinical benefit comparable with other available drugs. • Trabectedin was well tolerated, with a safety profile consistent with previous experiences. [ABSTRACT FROM AUTHOR]

Skin metastasis of ovarian cancer is extremely rare. We report an unusual case of ovarian carcinosarcoma with cutaneous metastasis of carcinomatous component that displayed distinct clinical manifestation. A 48-year-old woman presented to the dermatologist complaining of a new onset of erythematous, plaque-like skin rash with multiple small nodules on the left inner thigh, the area measuring 8 × 5cm. While the patient had no history of dermatologic conditions, she underwent a total hysterectomy and bilateral salpingo-oophorectomy, omentectomy, and lymph node dissection 16 months ago with a pathology confirmed stage IIIC ovarian carcinosarcoma. Of note, the carcinomatous component, mainly adenocarcinoma with hybrid features of seromucinous, endometrioid and minor high-grade serous carcinoma, involved bilateral fallopian tubes, omentum, and parametrium with extensive lymph node metastases. A skin biopsy specimen revealed an adenocarcinoma involving epidermis, dermis, and subcutaneous tissue with nodular contours, consistent with metastatic carcinomatous component of carcinosarcoma. Both carcinomatous component of primary ovarian carcinosarcoma and metastatic adenocarcinoma in the skin demonstrated Pax8, WT-1, and ER positivity and a mutation pattern of p53. The patient passed away 15 months after identification of skin metastasis. This case represents a unique example of cutaneous metastasis of ovarian carcinosarcoma with distinct clinical manifestation and detailed histopathological description. Alertness to the possibility of cutaneous metastasis, in combination with clinical history, morphological and immunohistochemical findings, is critical for a definitive classification. [ABSTRACT FROM AUTHOR]

Ovarian carcinosarcoma (OCS) is a rare, highly aggressive and rapidly progressing malignant tumor with an extremely poor prognosis. So far, due to the low incidence of OCS, there are no large-scale prospective studies exploring the standard care of OCS patients. There is no uniform and effective treatment for OCS. Within the development of precision medicine, targeted therapies (such as PARP inhibitors) have been widely used in epithelial ovarian cancer and various other solid tumors. Here, we report a BRCAwt patient with advanced OCS who experienced a second and a third cytoreductive surgery in June 2017 and October 2019 and has been on niraparib maintenance therapy for more than 20 months after receiving second-line and third-line chemotherapy. [ABSTRACT FROM AUTHOR]

Abstract Leptomeningeal metastasis is extremely rare in patients with ovarian cancer, but should be considered in patients presenting with neurologic deficits such as cauda equine syndrome. Given its poor prognosis and lack of data currently on management, additional studies are needed to optimize treatment regimens and improve outcomes.

Ovarian carcinosarcoma (OCS) is a rare, highly aggressive and rapidly progressing malignant tumor with an extremely poor prognosis. So far, due to the low incidence of OCS, there are no large-scale prospective studies exploring the standard care of OCS patients. There is no uniform and effective treatment for OCS. Within the development of precision medicine, targeted therapies (such as PARP inhibitors) have been widely used in epithelial ovarian cancer and various other solid tumors. Here, we report a BRCAwt patient with advanced OCS who experienced a second and a third cytoreductive surgery in June 2017 and October 2019 and has been on niraparib maintenance therapy for more than 20 months after receiving second-line and third-line chemotherapy.

Summary: Formalin-fixed paraffin embedding (FFPE) is the most widespread long-term tissue preservation approach. Here, we report a procedure to perform genome-wide spatial analysis of mRNA in FFPE-fixed tissue sections, using well-established, commercially available methods for imaging and spatial barcoding using slides spotted with barcoded oligo(dT) probes to capture the 3′ end of mRNA molecules in tissue sections. We applied this method for expression profiling and cell type mapping in coronal sections from the mouse brain to demonstrate the method’s capability to delineate anatomical regions from a molecular perspective. We also profiled the spatial composition of transcriptomic signatures in two ovarian carcinosarcoma samples, exemplifying the method’s potential to elucidate molecular mechanisms in heterogeneous clinical samples. Finally, we demonstrate the applicability of the assay to characterize human lung and kidney organoids and a human lung biopsy specimen infected with SARS-CoV-2. We anticipate that genome-wide spatial gene expression profiling in FFPE biospecimens will be used for retrospective analysis of biobank samples, which will facilitate longitudinal studies of biological processes and biomarker discovery.

Ovarian cancer, although not among the most commonly diagnosed cancers, remains a significant cause of cancer-related mortality in females. Several paraneoplastic syndromes have been associated, and this case study represents a rare manifestation of ovarian cancer, presenting as non-islet cell tumor hypoglycemia (NICTH), characterized by the excessive production of insulin-like growth factor-II (IGF-II) by tumor cells. We report a 55-year-old woman who presented to our hospital with abdominal distension and severe refractory hypoglycemia. The laboratory data revealed the suppression of serum insulin and C-peptide levels. The insulin-like growth factor II (IGF-II)/insulin-like growth factor 1 (IGF1) ratio was >32. The hypoglycemia was hence attributed to the non-islet cell tumor type, and it is likely driven by tumoral secretion of incompletely processed IGF-II. The lab findings suggested the existence of NICTH. Abdominal computed tomography demonstrated the presence of a left ovarian mass and peritoneal carcinomatosis. CT-guided biopsy of the peritoneal lesions showed poorly differentiated malignancy consistent with ovarian carcinosarcoma (OCS). The patient was treated with a continuous infusion of glucose. She even received oral prednisone and glucagon infusion. Chemotherapy with carboplatin and paclitaxel was initiated, but unfortunately, she died from complications of multiorgan failure. To our knowledge, this is the first novel case of an initial presentation of metastatic OCS with NICTH, underscoring the complexity of ovarian cancer presentations and the necessity of a comprehensive approach in managing rare paraneoplastic syndromes, such as NICTH., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Elemian et al.)

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Abstract Background Ovarian carcinosarcoma, which contains sarcomatous and carcinomatous components, is a very rare tumor. The carcinomatous component is often adenocarcinoma, and squamous cell carcinoma is extremely rare. We herein report a case of ovarian carcinosarcoma in which the carcinomatous component was squamous cell carcinoma. Case presentation A 68-year-old woman presented with a huge ovarian tumor with a clinical diagnosis of malignant tumor of the ovary. She underwent hysterectomy, bilateral adnexectomy, omentectomy and lymphadenectomy. Histologically, the tumor cells showed undifferentiated pleomorphic sarcoma as the sarcomatous component and squamous cell carcinoma as the carcinomatous component. The final diagnosis was ovarian carcinosarcoma with squamous cell carcinoma in the carcinomatous component, stage IIIA1. Postoperatively, the patient was treated with six cycles of combination chemotherapy with paclitaxel and carboplatin as adjuvant therapy. The patient was free of disease at 45 months’ follow-up consultation. Conclusion This is a rare report of ovarian carcinosarcoma with an epithelial component composed of squamous cell carcinoma. Combination chemotherapy with paclitaxel and carboplatin may be an effective choice as adjuvant chemotherapy in cases of ovarian carcinosarcoma including squamous cell carcinoma.

Objective: This study aimed to evaluate mesothelin (MSLN) expression and determine its clinical significance and correlation with human epidermal growth factor receptor 2 (HER2) expression in gynecological carcinosarcoma., Methods: We retrospectively evaluated patients with uterine carcinosarcoma (UCS) and ovarian carcinosarcoma (OCS) who underwent surgery between 1997 and 2019. Immunohistochemical staining of formalin-fixed, paraffin-embedded specimens for MSLN (clone SP74) and HER2 (clone 4A5) was also performed. MSLN was scored using the H-score and 4-tired scoring system (0-3+). MSLN positivity was defined as any positive cell at any intensity, while high MSLN expression was defined as an intensity of ≥2+ in ≥30% of tumor cells. HER2 expression was scored according to modified 2018 American Society of Clinical Oncology/College of American Pathologists criteria., Results: A total of 128 patients were recruited, including 119 with UCS and 9 with OCS. All cases in UCS exhibited MSLN positivity, and 33.9% showed high-MSLN expression. Clinicopathological characteristics were not significantly associated with high or low-MSLN expression. However, the high-MSLN group showed more prolonged overall survival (OS) than the low-MSLN group (not assessed vs. 36.8 months; hazard ratio=0.48, 95% confidence interval=0.26-0.89, p=0.016). HER2-high patients had higher MSLN expression than HER2-negative patients. In high-MSLN and low-MSLN expression groups, HER2 status did not affect OS. OCS showed 100% MSLN positivity, with 66.6% high-MSLN., Conclusion: MSLN expression is widely observed in gynecological carcinosarcomas. Moreover, high-MSLN expression is a favorable prognostic factor for UCS. MSLN could be a promising therapeutic target for UCS, even in the era of anti-HER2 therapy., Competing Interests: Kan Yonemori reports receiving grants or contracts from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ, USA), Daiichi-Sankyo, AstraZeneca, Taiho, Pfizer, Novartis, Takeda, Chugai, Ono, Seattle Genetics, Eisai, Eli Lilly, Genmab, Boehringer Ingelheim, Kyowa Hakko Kirin, Nihon Kayaku, Sanofi and Haihe. He also reports receiving honoraria for lectures, presentations, and speakers' bureaus for Pfizer, Eisai, AstraZeneca, Eli lilly, Takeda, Chugai, MSD, FujiFilm Pharma, Bayer, Asteras, Boehringer Ingelheim, Daiichi-Sankyo, PDR Pharma and Sanofi., (© 2024. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Abstract Background The optimal first-line chemotherapy for ovarian carcinosarcoma has not yet been determined. We therefore sought to determine the progression-free survival (PFS) and overall survival (OS) for patients with ovarian carcinosarcoma treated at our institution with different first-line chemotherapy regimens. Methods This single-institution, retrospective analysis included all patients with ovarian or primary peritoneal carcinosarcoma diagnosed from September 1996 to July 2017. Kaplan Meier analysis with a log-rank Mantel-Cox test was used to compare PFS and OS between treatment groups, and a p-value of

Leptomeningeal metastasis is extremely rare in patients with ovarian cancer, but should be considered in patients presenting with neurologic deficits such as cauda equine syndrome. Given its poor prognosis and lack of data currently on management, additional studies are needed to optimize treatment regimens and improve outcomes. [ABSTRACT FROM AUTHOR]

Ovarian carcinosarcoma, also referred as malignant mixed Mullerian tumour, is an uncommon, highly aggressive and malignant neoplasm which makes up 1 to 4% of all ovarian tumours. It is biphasic involving both malignant sarcomatous (mesenchymal) and carcinomatous (epithelial) cells. There are various subtypes such as serous and endometrioid. However, the mesenchymal part is sarcomatous. About 90% of cases of ovarian carcinosarcoma spread outside the ovary. The two most accepted theories of origin for carcinosarcoma of the ovary are the collision and conversion theories. A third theory is the combination theory. Prognosis remains poor even when still localised in the ovary. In the last few years, there has been no change in the survival rate. The median survival rate is lower than 2 years. Clinical features mainly include lower abdominal pain and a palpable abdominal mass. Ovarian carcinosarcoma remains poorly understood and understudied. Being a rare tumour, elaborate therapeutic consensus is not available for ovarian carcinosarcoma. The main treatment involves cytoreductive surgery and then chemotherapy. The type of chemotherapy, role of radiotherapy and novel therapies need to be further studied. The main objective of this article is to review the current literature on carcinosarcoma of the ovary.

Objectives: Ovarian carcinosarcomas are rare and aggressive ovarian malignancies. The objective of this study was to examine the current authors' experiences with optimal cytoreductive surgery (CRS) and platinum-based chemotherapy for managing ovarian carcinosarcomas. Materials and Methods: A retrospective study was carried out on 20 patients who had ovarian carcinosarcoma (OCS) and who underwent primary surgery at the Rajiv Gandhi Cancer Institute and Research Centre, in Delhi, India, from January 2004 till December 2016. Results: Complete cytoreduction to no gross residual disease was achieved in 14 patients, 10 patients had heterologous histologies with sarcomatous components, and 13 patients had advanced stage (stages III and IV) disease. Fifteen patients received platinum-based adjuvant chemotherapy. Follow-up periods ranged from 15 days to 82 months. After primary surgery, 9 patients developed recurrences and 4 had progressive disease. Ten patients died of disease during the follow-up period. The 3-year disease-free survival was 33%, and the 3-year overall survival (OS) was 40.52%. Homologous histology with sarcomatous components and optimal CRS were associated with significant improvements in OS, in a univariate analysis. However, in a multivariate analysis, only optimal surgery retained significance. Conclusions: Radical surgery resulting in no visible disease, followed by platinum-based chemotherapy appears to improve outcomes and survival in patients with OCS. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Ovarian carcinosarcoma (OCS) constitute uncommon malignancies accounting for only 1–4% of ovarian cancers. Patients more often present with advanced stage disease and symptoms similar to those of epithelial ovarian cancers (EOC). Optimal tumor cytoreduction appears to be an important determinant of survival. Platinum-based chemotherapy remains the most commonly employed adjuvant treatment. The uncertain origin and poor prognosis of OCS motivate determination of the molecular basis of carcinosarcomas aggressive behavior in the hope of developing novel and effective treatment modalities. The present review summarizes the current knowledge on the epidemiology, pathology, prognostic factors, clinical presentation, and therapeutic interventions including future potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Introduction. Ovarian carcinosarcoma (OCS), also known as malignant mixed Müllerian tumour (MMMT), is one of the rarest histological subtypes of ovarian cancer. It is an aggressive tumour with a dismal prognosis—the median survival of patients is less than two years. The rarity of the disease generates many controversies about histogenesis, prognostic factors and treatment of OCS. Histologically, OCS is composed of an epithelial and sarcomatous component. Case report. In the present case, a patient with bilateral ovarian cysts and bulky paraaortic lymph nodes is reported. Retroperitoneal paraaortic lymph node metastases were the only extrapelvic dissemination of OCS. The patient underwent comprehensive surgical staging procedures, including total abdominal hysterectomy and bilateral salpingo-oophorectomy, supracolic omentectomy and selective para-aortic lymphadenectomy. Histologically the ovarian carcinosarcoma was composed of an epithelial component (high-grade serous adenocarcinoma) and three sarcomatous components (homologous—endometrial stromal cell sarcoma, and heterologous—chondrosarcoma, rhabdomyosarcoma). Immunohistochemistry staining was performed. A postoperative complication (adhesion between the abdominal aorta and terminal ileum causing obstructive ileus) that has never been reported in the medical literature occurred. Conclusion. Carcinosarcomas are carcinomas with epithelial–mesenchymal transition and heterologous differentiation. Retroperitoneal pelvic and paraaortic lymph nodes should be carefully inspected in patients with ovarian tumours. Adhesions between the small bowels and abdominal aorta are possible complications after lymph node dissection in the paraaortic region.

A rare clinical case of bilateral carcinosarcoma of the ovary including a rare combination of serous adenocarcinoma and endometrial stromal sarcoma has been presented.

Objective: The purpose of this retrospective study was to compare the prognoses of women with ovarian carcinosarcoma (OCS) who had optimal cytoreductive surgery followed by platinum plus taxane combination chemotherapy to those of women with ovarian high-grade serous carcinoma (HGSC) treated in the same manner.Methods: A multicenter, retrospective department database review was performed to identify patients with OCS at eight gynecologic oncology centers in Turkey. A total of 54 women with OCS who had undergone optimal cytoreductive surgery followed by platinum plus taxane combination chemotherapy between 1999 and 2017 were included in this case-control study. Each case was matched to two women with ovarian HGSC who had undergone optimal cytoreductive surgery followed by platinum plus taxane combination chemotherapy. The Kaplan-Meier method was used to generate survival data. Factors predictive of outcome were analysed using Cox proportional hazards models.Results: Median disease-free survival (DFS) was 29 months [95% confidence interval (CI) 0-59, standard error (SE) 15.35] versus 27 months (95% CI 22.6-31.3, SE 2.22; p = 0.765) and median overall survival (OS) was 62 versus 82 months (p = 0.53) for cases and controls, respectively. For the entire cohort, the presence of ascites [hazard ratio (HR) 2.32; 95% CI 1.02-5.25, p = 0.04] and platinum resistance [HR 5.05; 95% CI 2.32-11, p < 0.001] were found to be independent risk factors for decreased OS.Conclusion: DFS and OS rates of patients with OCS and HGSC seem to be similar whenever optimal cytoreduction is achieved and followed by platinum plus taxane combination chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Carcinosarcoma of the ovary (CSO) is a rare and aggressive variant of ovarian cancer. Due to the rare nature of the disease there is insufficient evidence to make recommendations regarding standard management and overall prognosis. Methods: An Institutional Review Board-approved study identified all our patients with CSO between January 2011 and May 2018. Demographic and outcome measures were abstracted from the medical records and tumor board files. Cox proportional hazard models, log rank tests, and comparisons of means were used to calculate significance (p < 0.05). Results: 27 women with CSO were identified. The median age at diagnosis was 65 years (range 48−91). Five women (18%) presented with early stage disease (Stage I or II) and 22 patients (82%) presented with late stage III or IV disease. Twenty patients (74%) received intravenous platinum-based combination chemotherapy. Seven patients did not receive chemotherapy during their treatment course. The median overall survival was 23 months (range 2−68 months). Overall survival was not significantly worsened by the stage of disease at diagnosis. There was no difference in survival based on the age at diagnosis, tobacco status or ethnicity (p > 0.05). Conclusion: This is one of the largest single institution experiences with CSO. The majority of our patients presented with advanced stage disease and received adjuvant platinum-based chemotherapy after cytoreductive surgery. The median overall survival of 23 months was not affected by the stage of the disease. The optimal management of this rare disease needs further study with collaborative, prospective multi-institutional trials.

Ovarian carcinosarcoma cancer is the most lethal form of gynecological malignancy, but the pathogenesis and biological function for this ovarian cancer remain unknown. We establishment the transgenic mouse model of K-rasG12Dp53loxP/loxP and found that K-ras mutation and p53 deletion within the ovarian surface epithelium gave rise to ovarian lesions with a hyperproliferation and endometrioid glandular morphology. Furthermore, double mutant ovaries formed ovarian carcinosarcomas that were high grade and poorly differentiated. Induction was widely metastatic and spread to abdominal organs including liver, spleen, and kidney at 4 wk. We also confirmed the role of K-rasG12D in ovarian cancer cell lines MCAS and PA-1 and showed that K-rasG12D overexpression strongly induced cell proliferation, migration, and invasion. The ovarian cancer model we developed recapitulates the specific tumor histomorphology and the probable mechanism of malignant transformation in endometriosis. [ABSTRACT FROM AUTHOR]

Ovarian carcinosarcomas are rare gynecological malignancies with high biological aggressiveness and poor outcomes when compared to their epithelial counterparts. However, it seems that the only way to offer a chance for cure for these patients is an aggressive surgical approach in order to achieve complete cytoreduction to no visible residual disease. We present a 57 year old woman who presented for diffuse pelvic pain and constipation and who was diagnosed with a large ruptured pelvic mass invading the recto-sigmoid colon. The patient was submitted to surgery, a total hysterectomy with bilateral adnexectomy en bloc with recto-sigmodian resection, pelvic and para-aortic lymph node dissection being performed. The histopathological studies confirmed the presence of an ovarian carcinosarcoma. [ABSTRACT FROM AUTHOR]

Ovarian carcinoma (OC) is an umbrella term for multiple distinct diseases (histotypes), each with their own developmental origins, clinical behaviour and molecular profile. Accordingly, OC management is progressing away from a one-size-fits all approach, toward more molecularly-driven, histotype-specific management strategies. Our knowledge of driver events in high grade serous OC, the most common histotype, has led to major advances in treatments, including PARP inhibitor use. However, these agents are not suitable for all patients, most notably for many of those with rare OC histotypes. Identification of additional targeted therapeutic strategies will require a detailed understanding of the molecular landscape in each OC histotype. Until recently, tumour profiling studies in rare histotypes were sparse; however, significant advances have been made over the last decade. In particular, reports of genomic characterisation in endometrioid, clear cell, mucinous and low grade serous OC have significantly expanded our understanding of mutational events in these tumour types. Nonetheless, substantial knowledge gaps remain. This review summarises our current understanding of each histotype, highlighting recent advances in these unique diseases and outlining immediate research priorities for accelerating progress toward improving patient outcomes. • Ovarian cancer comprises multiple distinct disease types. • Each ovarian cancer type has unique clinical and molecular features. • Substantial advances have been made in our understanding of rare ovarian cancers. • Molecular understanding has led to targeted therapies for some ovarian cancers. • Significant gaps remain in our understanding of rare ovarian cancers. [ABSTRACT FROM AUTHOR]

Carcinosarcomas (CSs) of the uterus and ovary are highly aggressive neoplasms containing both carcinomatous and sarcomatous elements. We analyzed the mutational landscape of 68 uterine and ovarian CSs by whole-exome sequencing. We also performed multiregion whole-exome sequencing comprising two carcinoma and sarcoma samples from six tumors to resolve their evolutionary histories. The results demonstrated that carcinomatous and sarcomatous elements derive from a common precursor having mutations typical of carcinomas. In addition to mutations in cancer genes previously identified in uterine and ovarian carcinomas such as TP53, PIK3CA, PPP2R1A, KRAS, PTEN, CHD4, and BCOR, we found an excess of mutations in genes encoding histone H2A and H2B, as well as significant amplification of the segment of chromosome 6p harboring the histone gene cluster containing these genes. We also found frequent deletions of the genes TP53 and MBD3 (a member with CHD4 of the nucleosome remodeling deacetylase complex) and frequent amplification of chromosome segments containing the genes PIK3CA, TERT, and MYC. Stable transgenic expression of H2A and H2B in a uterine serous carcinoma cell line demonstrated that mutant, but not wild-type, histones increased expression of markers of epithelial-mesenchymal transition (EMT) as well as tumor migratory and invasive properties, suggesting a role in sarcomatous transformation. Comparison of the phylogenetic relationships of carcinomatous and sarcomatous elements of the same tumors demonstrated separate lineages leading to these two components. These findings define the genetic landscape of CSs and suggest therapeutic targets for these highly aggressive neoplasms. [ABSTRACT FROM AUTHOR]