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.

Compartment-specific multiomic profiling identifies SRC and GNAS as candidate drivers of epithelial-to-mesenchymal transition in ovarian carcinosarcoma.

BACKGROUND: Ovarian carcinosarcoma (OCS) is an exceptionally aggressive and understudied ovarian cancer type harbouring distinct carcinomatous and sarcomatous compartments. Here, we seek to identify shared and compartment-specific events that may represent potential therapeutic targets and candidate drivers of sarcomatous compartment formation through epithelial-to-mesenchymal transition (EMT). METHODS: We performed multiomic profiling (exome sequencing, RNA-sequencing, microRNA profiling) of paired carcinomatous and sarcomatous components in 12 OCS cases. RESULTS: While paired sarcomatous and carcinomatous compartments demonstrate substantial genomic similarities, multiple loci are recurrently copy number-altered between components; regions containing GNAS and SRC are recurrently gained within the sarcomatous compartment. CCNE1 gain is a common event in OCS, occurring more frequently than in high grade serous ovarian carcinoma (HGSOC). Transcriptomic analysis suggests increased MAPK activity and subtype switching toward poor prognosis HGSOC-derived transcriptomic subtypes within the sarcomatous component. The two compartments show global differences in microRNA profiles, with differentially expressed microRNAs targeting EMT-related genes (SIRT1, ZEB2) and regulators of pro-tumourigenic pathways (TGFß, NOTCH); chrX is a highly enriched target of these microRNAs and is also frequently deleted across samples. The sarcomatous component harbours significantly fewer CD8-positive cells, suggesting poorer immune engagement. CONCLUSION: CCNE1 gain and chrX loss are frequent in OCS. SRC gain, increased GNAS expression and microRNA dysregulation represent potential mechanisms driving sarcomatous compartment formation.

Nucleobindin-2 Mediates Transforming Growth Factor-ß1-Driven Phenotypes in Zinc Finger E-Box Binding Homeobox 1-High Uterine Carcinosarcoma.

Epithelial-mesenchymal transition is a hallmark of uterine carcinosarcoma (UCS). Here, shotgun proteomics analysis used to identify biomarkers associated with blebbistatin-mediated epithelial-mesenchymal transition in UCS indicated up-regulation of nucleobindin-2 (NUCB2) in endometrial carcinoma (Em Ca) cells. Expression of N-cadherin, Snail, Slug, and ZEB1 was reduced in NUCB2 knockout Em Ca cells, whereas ZEB1, Twist1, and vimentin were up-regulated in NUCB2-overexpressing Em Ca cells. NUCB2 knockout reduced cell proliferation and migration, whereas NUCB2 overexpression had the opposite effect. Treatment of Em Ca cells with transforming growth factor (TGF)-ß1 dramatically altered morphology toward a fibroblastic appearance; concomitantly, expression of NUCB2 and ZEB1 increased. The NUCB2 promoter was also activated by transfection of Smad2. In UCS tissues, NUCB2 expression was significantly higher in sarcomatous compared with carcinomatous components, which was consistent with increased TGF-ß1 mRNA expression in stromal and sarcomatous components compared with carcinomatous components. In addition, NUCB2 score correlated positively with ZEB1 and vimentin scores, whereas ZEB1 score correlated positively with Slug and vimentin scores and inversely with the E-cadherin score. Collectively, these data indicate that TGF-ß-dependent up-regulation of NUCB2 and ZEB1 contributes to the phenotypic characteristics of sarcomatous components in UCS.

Surgically resected sarcomatoid carcinoma of the lung: a nationwide retrospective study in 2010.

BACKGROUND: Sarcomatoid carcinoma of the lung is a rare histological type of non-small cell lung cancer with a poor prognosis. We aimed to investigate the clinicopathological characteristics and prognostic factors of surgically resected sarcomatoid carcinoma of the lung. METHODS: We retrospectively reviewed 14999 patients who underwent surgical resection for non-small cell lung cancer accumulated by the Japanese Joint Committee of Lung Cancer Registry in 2010. Clinicopathological characteristics and survival were compared between the sarcomatoid carcinoma and other non-small cell cancer groups. The prognostic factors in the sarcomatoid carcinoma group were identified using a multivariate Cox proportional hazard model. RESULTS: Patients with sarcomatoid carcinoma comprised 1.4% of all patients. The sarcomatoid carcinoma group demonstrated a more aggressive pathology with presentation at more advanced stages, requiring more frequent extensive surgical resections. The sarcomatoid carcinoma group had remarkably poorer overall and recurrence-free survival than the other non-small cell lung cancer group. Adjuvant chemotherapy was associated with improved survival for pathological stage II-III sarcomatoid carcinoma cases rather than for pathological stage I disease. In the multivariate analysis, larger tumor size, lymphatic permeation, and no adjuvant chemotherapy were associated with the sarcomatoid carcinoma group's overall and recurrence-free survival. CONCLUSIONS: Surgically resected sarcomatoid carcinoma of the lung has a higher aggressive and metastatic potential and a worse prognosis than other non-small cell lung cancers. Adjuvant chemotherapy, which was associated with enhanced survival in patients with pathological stage II-III of the disease, could be considered for treating patients with pathological stage II-III sarcomatoid carcinoma of the lung.

Social determinants of health in uterine carcinosarcoma.

OBJECTIVE: UCS survival outcome disparities by race have been reported. We aimed to investigate social determinants of health (SDOH) and their relation to survival outcomes in women at two affiliated high-volume institutions serving a racially and economically diverse population. METHODS: Women diagnosed with stage I-IV UCS treated at St. Paul University Hospital, University of Texas Southwestern (UTSW) Zale Lipshy Pavilion-William P. Clements Jr. University Hospital, and Parkland Memorial Hospital between 1992 and 2022 were eligible. Patients were identified by the local tumor registries; a retrospective study was conducted. The Pearson chi-square test was utilized for categorical variables. OS and PFS were calculated using Kaplan-Meier estimates and compared with the log-rank test. Multivariate Cox models were used to identify independent prognostic factors. All statistical analyses were performed using SAS, version 9.4. RESULTS: Over half of the 218 patients with UCS were NHB. 35% of the patients had stage IV disease. Most HSP and NHB patients had a lower median household income* than Asian/Pacific Islander (API) or NHW (p < 0.001). Stage at diagnosis significantly affected OS (p < 0.001) but not PFS (p = 0.46) in univariate analyses. Accounting for age at diagnosis, insurance, income*, hospital, distance between hospital and home, months from diagnosis to first treatment, stage, and adjuvant therapy, race was significant for OS (p = 0.03) and PFS (p = 0.04). *Median household income by ZIP Code. CONCLUSIONS: Racial disparities were seen in median household income. Most SDOH independently analyzed in this study did not affect OS. The complex interaction between race and stage in UCS survival outcomes needs further investigation.

Molecular landscape of ERBB2/HER2 gene amplification among patients with gynecologic malignancies; clinical implications and future directions.

OBJECTIVE: Investigate the prevalence of ERBB2/HER2 gene amplification among patients with gynecologic malignancies. METHODS: The American Association of Cancer Research (AACR) Genomics Evidence of Neoplasia Information Exchange (GENIE) (version 13.1) database was accessed and patients with endometrial, ovarian, and cervical cancer were identified. Patients with available data on the presence of copy-number gene alterations were selected for further analysis. Incidence of ERBB2 amplification following stratification by tumor site and histology was evaluated. Data from the OncoKB database, as provided by cBioPortal, was utilized to determine presence of pathogenic genomic alterations. RESULTS: A total of 6961 patients who met the inclusion criteria were identified: 49.1% with ovarian cancer, 45.2% with endometrial cancer and 5.7% with cervical cancer respectively. Overall incidence of ERBB2 amplification was 3.8%. Highest incidence of ERBB2 amplification was observed among patients with mucinous ovarian (14.4%), uterine serous (13.2%), uterine clear cell (9.4%), and uterine carcinosarcoma (7.9%). ERBB2 amplification was rare among patients with TP53 wild-type endometrioid endometrial cancer (0.4%). High incidence of mutations in genes of the PI3K pathway was observed among patients with ERBB2 amplified tumors. CONCLUSION: ERBB2 amplification is frequently encountered among patients with uterine serous carcinoma, and mucinous ovarian carcinoma. In addition, a high incidence was also observed among those with uterine clear cell carcinoma, and uterine carcinosarcoma. For patients with endometrioid endometrial carcinoma, incidence of ERBB2 amplification is low, especially in the absence of TP53 mutations.

Racial, ethnic and country of origin disparities in aggressive endometrial cancer histologic subtypes.

OBJECTIVE: This study investigated the risk of an aggressive endometrial cancer (EC) diagnosis by race, ethnicity, and country of origin to further elucidate histologic disparities in non-Hispanic Black (NHB), Hispanic, Asian/Pacific Islander (API), American Indian/Alaskan Native (AIAN) vs. non-Hispanic White (NHW) patients, particularly in Hispanic or API subgroups. METHODS: Patient diagnosed between 2004 and 2020 with low grade (LG)-endometrioid endometrial cancer (ECC) or an aggressive EC including grade 3 EEC, serous carcinoma, clear cell carcinoma, mixed epithelial carcinoma, or carcinosarcoma in the National Cancer Database were studied. The odds ratio (OR) and 95% confidence interval (CI) for diagnosis of an aggressive EC histology was estimated using logistic modeling. RESULTS: There were 343,868 NHW, 48,897 NHB, 30,013 Hispanic, 15,015 API and 1646 AIAN patients. The OR (95% CI) for an aggressive EC diagnosis was 3.07 (3.01-3.13) for NHB, 1.08 (1.06-1.11) for Hispanic, 1.17 (1.13-1.21) for API and 1.07 (0.96-1.19) for AIAN, relative to NHW patients. Subset analyses by country of origin illustrated the diversity in the OR for an aggressive EC diagnosis among Hispanic (1.18 for Mexican to 1.87 for Dominican), Asian (1.14 Asian Indian-Pakistani to 1.48 Korean) and Pacific Islander (1.00 for Hawaiian to 1.33 for Samoan) descendants. Hispanic, API and AIAN patients were diagnosed 5-years younger that NHW patients, and the risk for an aggressive EC histology were all significantly higher than NHW patients after correcting for age. Insurance status was another independent risk factor for aggressive histology. CONCLUSIONS: Risk of an aggressive EC diagnosis varied by race, ethnicity, and country of origin. NHB patients had the highest risk, followed by Dominican, South/Central American, Cuban, Korean, Thai, Vietnamese, and Filipino descendants.

Preclinical in vitro and in vivo activity of the RAF/MEK clamp avutometinib in combination with FAK inhibition in uterine carcinosarcomas.

OBJECTIVES: Uterine carcinosarcomas (UCS) are rare, biologically aggressive tumors. Since UCS may harbor mutations in RAS/MAPK pathway genes we evaluated the preclinical in vitro and in vivo efficacy of the RAF/MEK clamp avutometinib in combination with the focal adhesion kinase (FAK) inhibitors defactinib or VS-4718 against multiple primary UCS cell lines and xenografts. METHODS: Whole-exome-sequencing (WES) was used to evaluate the genetic landscape of 5 primary UCS cell lines. The in vitro activity of avutometinib ± FAK inhibitor was evaluated using cell viability and cell cycle assays against primary UCS cell lines. Mechanistic studies were performed using western blot assays while in vivo experiments were completed in UCS tumor bearing mice treated with avutometinib ± FAK inhibitor by oral gavage. RESULTS: WES results demonstrated multiple UCS cell lines harbor genetic alterations including KRAS, PTK2, BRAF, MAP2K, and MAP2K1, potentially sensitizing to FAK and RAF/MEK inhibition. Four out of five of the UCS cell lines demonstrated in vitro sensitivity to FAK and/or RAF/MEK inhibition when used alone or in combination. By western blot assays, exposure of UCS cell lines to the combination of defactinib/avutometinib demonstrated decreased phosphorylated (p)-FAK as well as decreased p-ERK. In vivo, the combination of avutometinib/VS-4718 demonstrated superior tumor growth inhibition and longer survival compared to single agent treatment and controls starting at day 10 (p < 0.002) in UCS xenografts. CONCLUSION: The combination of avutometinib and defactinib demonstrates promising in vitro and in vivo anti-tumor activity against primary UCS cell lines and xenografts.

Endometrial Carcinosarcomas are Almost Exclusively of p53abn Molecular Subtype After Exclusion of Mimics.

SUMMARY: Our aim was to assess the molecular subtype(s) and perform a detailed morphologic review of tumors diagnosed as carcinosarcoma in a population-based cohort. Forty-one carcinosarcomas were identified from a cohort of 973 endometrial carcinomas diagnosed in 2016. We assessed immunostaining and sequencing data and undertook expert pathology reviews of these cases as well as all subsequently diagnosed (post-2016) carcinosarcomas of no specific molecular profile (NSMP) molecular subtype (n=3) from our institutions. In the 2016 cohort, 37 of the 41 carcinosarcomas (91.2%) were p53abn, 2 (4.9%) were NSMP, and 1 each (2.4%) were POLE mut and mismatch repair deficiency molecular subtypes, respectively. Of the 4 non-p53abn tumors on review, both NSMP tumors were corded and hyalinized (CHEC) pattern endometrioid carcinoma, the mismatch repair deficiency tumor was a grade 1 endometrioid carcinoma with reactive stromal proliferation, and the POLE mut tumor was grade 3 endometrioid carcinoma with spindle cell growth, that is, none were confirmed to be carcinosarcoma on review. We found 11 additional cases among the 37 p53abn tumors that were not confirmed to be carcinosarcoma on the review (3 undifferentiated or dedifferentiated carcinomas, 5 carcinomas with CHEC features, 2 carcinomas showing prominent reactive spindle cell stroma, and 1 adenosarcoma). In the review of institutional cases reported as NSMP carcinosarcoma after 2016, 3 were identified (1 adenosarcoma and 2 mesonephric-like adenocarcinoma on review). In this series, all confirmed endometrial carcinosarcomas were p53abn. The finding of any other molecular subtype in a carcinosarcoma warrants pathology review to exclude mimics.

Rare malignant neoplasm of the esophagus: current status and future perspectives.

Esophageal cancer is common worldwide, including in Japan, and its major histological subtype is squamous cell carcinoma. However, there are some rare esophageal cancers, including neuroendocrine neoplasm, gastrointestinal stromal tumor, carcinosarcoma and malignant melanoma. The biological and clinical features of these cancers differ from those of esophageal squamous cell carcinoma. Therefore, different treatment strategies are needed for these cancers but are based on limited evidence. Neuroendocrine neoplasm is mainly divided into neuroendocrine tumor and neuroendocrine carcinoma by differentiation and the Ki-67 proliferation index or mitotic index. Epidemiologically, the majority of esophageal neuroendocrine neoplasms are neuroendocrine carcinoma. The treatment of neuroendocrine carcinoma is similar to that of small cell lung cancer, which has similar morphological and biological features. Gastrointestinal stromal tumor is known to be associated with alterations in the c-KIT and platelet-derived growth factor receptor genes and, if resectable, is treated in accordance with the modified Fletcher classification. Carcinosarcoma is generally resistant to both chemotherapy and radiotherapy and requires multimodal treatments such as surgery plus chemotherapy to achieve cure. Primary malignant melanoma is resistant to cytotoxic chemotherapy, but immune checkpoint inhibitors have recently demonstrated efficacy for malignant melanoma of the esophagus. This review focuses on the current status and future perspectives for rare cancer of the esophagus.

Teratoma combined with struma ovarii and sarcomatoid carcinoma: a case report and review of the literature.

This is a rare case of struma ovarii combined with sarcomatoid carcinoma. Because struma ovarii and ovarian sarcomatoid carcinoma have an extremely low incidence, this may be the first case of a combined occurrence of both. Therefore, this report describes its clinical manifestations, diagnosis, and treatment, analyzes the pathogenesis, and summarizes the previous literature in the hope that it can be helpful to other tumor-related medical personnel and provide material support for the formation of guidelines for this disease.

Uterine serous carcinoma and uterine carcinosarcoma: molecular features, clinical advances, and emerging therapies.

Endometrial cancer, including high-grade subtypes, has a rising incidence and mortality. Uterine serous carcinoma (USC) and uterine carcinosarcoma (UCS) make up a small but increasing proportion of endometrial cancer cases and account for a significant portion of endometrial cancer mortality. Despite being molecularly and clinically distinct, both USC and UCS have a poor prognosis. Thus far, there have been few therapeutic strategies directed at these endometrial cancer subtypes. This review summarizes the genomic and molecular features of USC and UCS, clinical advances in the treatment of primary advanced and recurrent endometrial cancer, and novel molecularly-driven treatment strategies.

Sarcoma of the uterine cervix: experience of a single center.

OBJECTIVES: To investigate the clinicopathological characteristics and prognosis of patients with primary sarcoma of the uterine cervix. METHODS: We identified all patients with primary cervical sarcomas treated at our institution from 2002 to 2020 and analyzed the clinicopathological characteristics and prognosis. RESULTS: 34 patients were identified, 7 (20.6%) patients had leiomyosarcoma, 6 (17.6%) had carcinosarcoma, 5 (14.7%) had Ewing sarcoma, 4 (11.8%) had rhabdomyosarcoma, 4 (11.8%) had undifferentiated sarcoma, 2 (5.9%) had adenosarcoma, 2 (5.9%) had endometrial stromal sarcoma, 1 (2.9%) had dermatofibrosarcoma protuberans, 1 (2.9%) had alveolar soft tissue sarcoma and 2 (5.9%) had sarcoma not otherwise specified. The median age of the whole patients was 43.5 years (range, 13-63). The median age of patients with Ewing sarcoma or rhabdomyosarcoma was 22 years (range, 13-39) and 17 years (range, 13-36 years), respectively. The distribution by stage was: stage I in 21 (61.8%) patients, stage II in 4 (11.8%), stage III in 6 (17.6%) and stage IV in 3 (8.8%). Overall, 30 patients (88.2%) received surgical treatment. The median follow-up was 33.3 months (range 3.6-187.3 months). 11 patients died within 2 years after diagnosis, most of them were patients with carcinosarcoma or undifferentiated sarcoma (45.5%, 5/11). In the entire cohort, 2- and 5-year OS were 67.2% and 56.9%, respectively. 5-year OS was 25.0% for undifferentiated sarcoma, 50.0% for rhabdomyosarcoma, 50.0% for carcinosarcoma, 53.3% for Ewing sarcoma, 57.1% for leiomyosarcoma. CONCLUSION: Cervical sarcomas are rare neoplasms with multiple histological subtypes and follow an aggressive course. Prognosis may be associated with tumor histology and stage.

Thymic carcinosarcoma with melanocytic differentiation in a dog.

Carcinosarcomas are very rare tumors in dogs. Although carcinosarcomas with melanocytic differentiation arising from organs other than the thymus have been described in humans, this type of tumor has not been reported in dogs in any part of the body. We observed such a tumor in the cranial mediastinum of an 11-year-old spayed female dachshund. The dog was admitted to the clinic because of coughing, sporadic regurgitation, and dyspnea. Thoracic ultrasonography and computed tomography revealed a large mediastinal mass that was surgically removed via sternotomy. The tumor was of thymic origin and demonstrated 3 distinct components: an epithelial component positive for pancytokeratin (AE1/AE3) and high molecular weight cytokeratin (CK5/CK6) with some cystic spaces; a mesenchymal component positive for vimentin; and in association with the epithelial part, a minor melanocytic component positive for Melan A. Histologic metastasis of the epithelial and melanocytic components was present within a tracheobronchial lymph node. The dog died 105 d after surgery, after an episode of acute dyspnea. Key clinical message: To the authors' knowledge, this is the first report of thymic carcinosarcoma with melanocytic differentiation.

Carcinosarcome thymique avec différenciation mélanocytaire chez un chienLes carcinosarcomes sont des tumeurs très rares chez le chien. Bien que des carcinosarcomes avec différenciation mélanocytaire provenant d'organes autres que le thymus aient été décrits chez l'homme, ce type de tumeur n'a été rapporté chez le chien dans aucune partie du corps. Nous avons observé une telle tumeur dans le médiastin cránien d'une femelle teckel stérilisée de 11 ans. Le chien a été admis à la clinique en raison de toux, de régurgitations sporadiques et de dyspnée. L'échographie thoracique et la tomodensitométrie ont révélé une masse médiastinale importante qui a été retirée chirurgicalement par sternotomie. La tumeur était d'origine thymique et présentait 3 composantes distinctes : une composante épithéliale positive pour la pancytokératine (AE1/AE3) et la cytokératine de haut poids moléculaire (CK5/CK6) avec quelques espaces kystiques; un composant mésenchymateux positif à la vimentine; et en association avec la partie épithéliale, un composant mélanocytaire mineur positif pour Melan A. Des métastases histologiques des composants épithéliaux et mélanocytaires étaient présentes dans un ganglion lymphatique trachéobronchique. Le chien est décédé 105 jours après l'intervention chirurgicale, à la suite d'un épisode de dyspnée aiguë.Message clinique clé :À la connaissance des auteurs, il s'agit du premier cas de carcinosarcome thymique avec différenciation mélanocytaire.(Traduit par Dr Serge Messier).

[Gallbladder carcinosarcoma associated with pancreaticobiliary maljunction with biliary dilation:a case report].

A 68-year-old female patient was referred to our hospital with acute cholangitis. Computed tomography revealed common bile duct dilatation, gallbladder fundal tumor, and gallbladder wall thickening attached to the tumor. Cholangiography revealed pancreaticobiliary maljunction with biliary dilation. The patient was diagnosed with pancreaticobiliary maljunction with biliary dilation and gallbladder cancer and underwent liver S4b+5 and bile duct resection and reconstruction. Pathological results revealed that the gallbladder fundal tumor included sarcoma, and the gallbladder wall thickening had adenocarcinoma;thus, the patient was diagnosed with gallbladder carcinosarcoma.

Ovarian Carcinoma: A Single-Centre Eight-Year Case-Series Study with Survival Analysis.

Introduction: This research describes an eight-year case-series of ovarian carcinoma by surgical (pTNM) staging and surgical procedure, explores the characteristics of ovarian surface epithelial cell (OSEC) tumours by histopathological type in a single centre of reference. Material and Methods: survival analysis with overall survivor probabilities for n=263 patients for 12 months and 60-month tumour free survival status (TFS). Results by staging (pTNM stage classification), histotype and for poor surgical candidate (PSC) status are shown. Histotype high grade serous carcinoma (HGSC) was the most frequently diagnosed type (63%). Results: 12-month survivor probabilities according to histotype, rank as follows: clear cell carcinoma (CCC) - 14%; rare carcinoma (RC) - 15%; carcinosarcoma (CS) - 29%; HGSC - 46%; low grade serous carcinoma (LGSC) - 74%; endometrioid carcinoma (EC) - 79%; mucinous carcinoma (MC) - 80% and borderline tumours (BLT) - 94%. At 60 months results are: RC and MC - 0%; CCC - 14%; HGSC - 16%; CS - 29%; LGSC - 62%; EC - 66%; and BLT - 94%. Overall median survival time is 26 months (CI95% 15 to 37); and 20 months when BLT excluded (CI95% CI 15 to 25). Conclusions: These results may guide further research for the OSEC pathology and its histotypes.

[Laryngeal carcinosarcoma]. / Kartsinosarkoma gortani.

A clinical case of a rare malignant tumor of the larynx, carcinosarcoma, is described. The features of the clinical picture, diagnostic methods: instrumental and morphological are presented.

Mesonephric-like adenocarcinoma of the female genital tract: novel observations and detailed molecular characterisation of mixed tumours and mesonephric-like carcinosarcomas.

AIMS: To report novel observations in five mesonephric-like adenocarcinomas (MLAs) of the female genital tract. METHODS AND RESULTS: We report two endometrial MLAs in association with endometrioid carcinoma and atypical hyperplasia and three (one endometrial, two ovarian) cases with a sarcomatoid component (mesonephric-like carcinosarcoma). Pathogenic KRAS mutations, which are characteristic of MLA, were identified in all cases although interestingly, in one of the mixed carcinomas, this was confined to the endometrioid component. The concurrent MLA, endometrioid carcinoma and atypical hyperplasia components in one case harboured identical EGFR, PTEN and CCNE1 mutations, suggesting that the atypical hyperplasia gave rise to a Müllerian carcinoma with both endometrioid and mesonephric-like components. The carcinosarcomas all contained a component of MLA and a sarcomatous component with chondroid elements. In the ovarian carcinosarcomas, the coexisting epithelial and sarcomatous components shared some mutations including KRAS and CREBBP, suggesting that they are clonally related. Furthermore, in one case CREBBP and KRAS mutations detected in the MLA and sarcomatous components were also detected in an associated undifferentiated carcinoma component, suggesting that it was clonally related to the MLA and sarcomatous components. CONCLUSIONS: Our observations provide additional evidence that MLAs have a Müllerian origin and characterise mesonephric-like carcinosarcomas in which chondroid elements appear to be characteristic. In reporting these findings, we provide recommendations for distinction between a mesonephric-like carcinosarcoma and a MLA with a spindle cell component.

Folate receptor alpha is widely expressed and a potential therapeutic target in uterine and ovarian carcinosarcoma.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Germline drivers of gynecologic carcinosarcomas.

OBJECTIVES: To describe the prevalence of germline pathogenic variants (gPVs) in endometrial and ovarian carcinosarcomas and determine if gPVs are drivers of carcinosarcoma. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.