Analysis of Prognostic Factors and Cancer-Specific Survival in Patients with Undifferentiated and Dedifferentiated Endometrial Carcinoma Undergoing Various Postoperative Adjuvant Therapies.

Purpose: To investigate prognostic factors affecting cancer-specific survival (CSS) and to analyze the survival outcomes of patients with undifferentiated and dedifferentiated endometrial carcinoma (UDEC) who underwent various postoperative adjuvant therapies. Methods: The independent risk factors affecting CSS were studied using univariate and multivariate Cox regression analysis, and CSS in the presence of various postoperative treatments was evaluated using Kaplan-Meier method based on the cohort with pathologically confirmed UDEC from the Surveillance, Epidemiology, and End Results (SEER) database. Meanwhile, the study included 18 cases with UDEC in our center and explored their molecular characteristics and prognosis. Results: Between 2000 and 2019, a total of 443 patients were included from the SEER database. The median CSS duration was 14 months, with corresponding 3- and 5-year CSS rates of 45.9% and 44.0%, respectively. Factors such as pTNM stage, surgical resection of primary lesion, and chemoradiation independently influenced CSS. Postoperative chemotherapy alone improved CSS in patients with initial tumor spread beyond the uterus (pT3 and pT4), or lymph node (LN) invasion, or distant metastases. Additionally, postoperative radiotherapy enhanced CSS in patients who had undergone postoperative chemotherapy, those with primary tumors progressing to stage pT3, and those with LN involvement but without distant metastases. Of the 18 patients diagnosed at our center, with a median follow-up of 15.5 months, one experienced relapse and two succumbed to UDEC, who exhibited aberrant p53 expression in immunohistochemical staining. Conclusion: Postoperative chemotherapy and radiotherapy are beneficial for UDEC patients with tumors extending beyond the uterus or involving lymph nodes.

Long-term disease-free survival with chemotherapy and pembrolizumab in a patient with unmeasurable, advanced stage dedifferentiated endometrial carcinoma.

Dedifferentiated endometrial carcinoma is a rare, highly aggressive subtype of endometrial cancer associated with poor survival outcomes. Current guidelines recommend treatment of advanced-stage disease with surgical staging or cytoreduction and platinum/taxane-based chemotherapy. Despite these approaches, the achievement of long-term remission or prolonged survival is challenging. Recent Phase III studies demonstrate that the addition of PD-1 inhibitors to standard chemotherapy significantly improves progression-free survival in patients with measurable, mismatch repair deficient (dMMR) and proficient (pMMR) advanced-stage or recurrent endometrial carcinoma. However, the role of PD-1 blockade in the treatment of undifferentiated and dedifferentiated endometrial carcinoma remains unclear, as very few patients with these cancer subtypes were included in the trials. In this case report, we present a patient with dMMR dedifferentiated endometrial carcinoma, treated with primary surgery to no gross residual disease, followed by carboplatin/paclitaxel chemotherapy and a short course of maintenance pembrolizumab. To date, the patient remains with a prolonged disease-free survival of 61 months, supporting the potential use of PD-1 inhibitors in the upfront treatment of unmeasurable, advanced-stage, dMMR dedifferentiated endometrial carcinoma.

Undifferentiated component of dedifferentiated endometrial carcinoma presenting as a "small round cell" malignancy in a mediastinal lymph node, mimicking small cell carcinoma.

Undifferentiated/dedifferentiated endometrial carcinoma is an uncommon malignant neoplasm of the endometrium that can present as a diagnostic challenge, especially in a metastatic setting. We present a case of a 70-year-old woman with a prior endometrial biopsy diagnosed as endometrioid carcinoma, FIGO Grade 2. Chest computerized tomography showed moderate to severe centrilobular emphysema with a 3 mm nodule in the right upper lobe and posterior mediastinal lymphadenopathy. Fine needle aspiration smears of the mediastinal lymph node showed predominantly single and loosely cohesive tumor cells with scant basophilic cytoplasm, prominent nuclear streaking, and molding. Inconspicuous nucleoli and mitotic figures were present. Immunohistochemical (IHC) stains showed the tumor cells were positive for CD56 and synaptophysin but negative for AE1/AE3, CAM5.2, CK7, CK20, TTF-1, INSM1, chromogranin, CD99, HMB45, SOX10, EBV-LMP1, and desmin. Flow cytometry was negative for lymphoma. Based on the overall cytologic findings and significant smoking history, a small cell carcinoma could not be excluded. Similar morphologic findings were identified on the corresponding lymph node biopsy. Because of the history of endometrial carcinoma, additional IHC stains (PAX 8, ER, and EMA) were done but were negative. However, the mismatch repair proteins revealed loss of MLH1 and PMS2 with retained MSH2 and MSH6 nuclear expression. Hence, a metastatic undifferentiated component of a dedifferentiated carcinoma from the patients' endometrial primary was favored and subsequently confirmed on the hysterectomy specimen.

Dedifferentiated endometrial carcinoma arising from serous carcinoma: Diagnostic challenges and recommendations.

•Dedifferentiated endometrial carcinoma arising from serous carcinoma (null-type P53).•Differential diagnosis including carcinosarcoma, FIGO grade 3 endometrioid carcinoma.•Also need to rule out SMARCA4-deficient uterine sarcoma and other sarcomas.

Undifferentiated-dedifferentiated endometrial carcinoma; the reappearance of an old friend with insights into the new data.

Endometrial carcinoma is a common malignancy in women and shows increasing incidence. Except for its two main pathogenetic types I and II, the continuing evolution on molecular genetics have led to a new classification system (TCGA), that includes four main molecular subtypes: (i) POLE-mutant (ultramutated), (ii) hypermutated (MSI), (iii) copy-number low/MSS (p53wt) and (iv) copy-number high/serous-like (p53mut). The undifferentiated and dedifferentiated endometrial carcinomas are rare and clinically aggressive variants, comprising about 10% of the high-grade endometrial carcinomas and 2% of the endometrial carcinomas in general. Until recently, they were under-recognized and not fully described morphologically and immunohistochemically/molecularly. Their recognition diagnostically is crucial because of their poor prognosis; approximately 40% of patients with these subtypes will die within 0.5-20 months after diagnosis, so additional therapeutic strategies are important for an effective management. Because of their rarity, the responsiveness to other than conventional treatment, such as immunotherapy, has not been sufficiently investigated yet. The aim of this review is to provide an update on the knowledge about these two uncommon subtypes according to the current literature.

ARID1A, BRG1, and INI1 deficiency in undifferentiated and dedifferentiated endometrial carcinoma: a clinicopathologic, immunohistochemical, and next-generation sequencing analysis of a case series from a single institution.

Undifferentiated/dedifferentiated endometrial carcinomas (UDEC and DDEC) are rare, aggressive uterine neoplasms, with no specific line of differentiation. A significant proportion of these cases feature mutations of SWI/SNF chromatin remodeling complex members, including ARID1A, SMARCA4, and SMARCB1 genes. To study these entities more comprehensively, we identified 10 UDECs and 10 DDECs from our pathology archives, obtained clinicopathologic findings and follow-up data, and performed immunohistochemical studies for ARID1A, BRG1 (SMARCA4), and INI1 (SMARCB1) proteins. In addition, we successfully conducted targeted next-generation sequencing for 23 samples, including 7 UDECs, and 7 undifferentiated and 9 well/moderately-differentiated components of DDECs. Cases consisted of 18 hysterectomies and 2 curettage/biopsy specimens. Patient age ranged from 47 to 77 years (median, 59 years), with a median tumor size of 8.0 cm (range, 2.5-13.0 cm). All cases demonstrated lymphovascular invasion and the majority (13/20) were FIGO stage III-IV. By immunohistochemistry, ARID1A loss was observed in 15 cases, BRG1 loss in 4, and all cases had intact INI1 expression. A trend for enrichment of the undifferentiated component of DDECs for ARID1A loss was seen, although not statistically significant. Sequencing revealed frequent pathogenic mutations in PTEN, PIK3CA, ARID1A, CTNNB1, and RNF43, a recurrent MAX pathogenic mutation, and MYC and 12p copy number gains. In DDECs, the undifferentiated component featured a higher tumor mutational burden compared to the well/moderately-differentiated component; however, the mutational landscape largely overlapped. Overall, our study provides deep insights into the mutational landscape of UDEC/DDEC, SWI/SNF chromatin remodeling complex member status, and their potential relationships with tumor features.

Uncommon and Difficult High-Grade Endometrial Carcinomas.

This article presents features of uncommon high-grade endometrial carcinomas that often pose a significant diagnostic challenge. An update on undifferentiated and dedifferentiated endometrial carcinoma is first provided, followed by discussions on more recently defined entities such as mesonephric-like carcinoma of the endometrium and gastric-type endometrial carcinomas. Finally, endometrial carcinoma with germ cell or trophoblastic-like components is discussed.

A Patient-Derived Xenograft Model of Dedifferentiated Endometrial Carcinoma: A Proof-of-Concept Study for the Identification of New Molecularly Informed Treatment Approaches.

Conventional treatment of dedifferentiated endometrial carcinoma (DEC)-an uncommon and highly aggressive uterine malignancy-is beset by high failure rates. A line of research that holds promise to overcome these limitations is tailored treatments targeted on specific molecular alterations. However, suitable preclinical platforms to allow a reliable implementation of this approach are still lacking. Here, we developed a patient-derived xenograft (PDX) model for preclinical testing of investigational drugs informed by molecular data. The model-termed PDX-mLung was established in mice implanted with lung metastatic lesions obtained from a patient with DEC. Histologic and whole-exome genetic analyses revealed a high degree of identity between PDX-mLung and the patient's parental lesions (both primary DEC and lung metastases). Interestingly, molecular analyses revealed that PDX-mLung harbored druggable alterations including a FGFR2 mutation and CCNE2 amplification. Targeted combined treatment with the FGFR inhibitor lenvatinib and the cell cycle inhibitor palbociclib was found to exert synergistic therapeutic effects against in vivo tumor growth. Based on the results of RNA sequencing, lenvatinib and palbociclib were found to exert anti-tumor effects by interfering interferon signaling and activating hormonal pathways, respectively. Collectively, these data provide proof-of-concept evidence on the value of PDX models for preclinical testing of molecularly informed drug therapy in difficult-to-treat human malignancies. Further clinical research is needed to examine more rigorously the potential usefulness of the lenvatinib and palbociclib combination in patients with DEC.

Clinico-pathological significance of TCGA classification and SWI/SNF proteins expression in undifferentiated/dedifferentiated endometrial carcinoma: A possible prognostic risk stratification.

BACKGROUND: Undifferentiated/dedifferentiated endometrial carcinoma (UEC/DDEC) is a heterogeneous entity, which may show any of the TCGA molecular signatures and loss of the switch/sucrose nonfermentable (SWI/SNF) proteins expression. AIM: To assess the clinico-pathological significance of the TCGA molecular groups and SWI/SNF proteins expression in UEC/DDEC, through a quantitative systematic review. METHODS: Electronic databases were searched for all studies assessing the TCGA molecular groups, i.e. POLE-mutant, mismatch repair-deficient (MMRd), p53-abnormal (p53abn) and no specific molecular profile (NSMP), and/or the SWI/SNF proteins (SMARCA4/BRG1, SMARCB1/INI1, ARID1B) expression in UEC/DDEC. Student t-test, Fisher's exact test and Kaplan-Meier survival analysis with long-rank test were used to assess differences among groups; a p-value<0.05 was considered significant. RESULTS: Eight studies were included in the systematic review. Among the TCGA groups, the mean patient age was significantly higher in the p53abn group than in the NSMP group (p = 0.048). The POLE-mutant group showed advanced FIGO stage (III-IV) significantly less commonly than the NSMP (p = 0.003) and MMRd (p = 0.008) groups, and a significantly better prognosis than the NSMP (p = 0.007), MMRd (p = 0.011) and p53abn (p = 0.045) groups.The SWI/SNF-deficient cases showed a significantly worse prognosis than the SWI/SNF-intact cases (p = 0.010), while no significant differences were found regarding patient age and FIGO stage. CONCLUSIONS: Among UEC/DDEC, POLE-mutant cases show good prognosis, while SWI/SNF-deficient cases show poor prognosis. The other TCGA molecular subtypes seem to be characterized by an intermediate biological behaviour. On this account, UEC/DDEC patients might be subdivided into three risk groups based on POLE and SWI/SNF status. Further studies are necessary in this field.

Magnetic resonance imaging findings in 11 cases of dedifferentiated endometrial carcinoma of the uterus.

PURPOSE: We evaluated magnetic resonance imaging (MRI) findings of dedifferentiated endometrial carcinoma (DEC), comprising undifferentiated carcinoma and low-grade endometrioid carcinoma. MATERIALS AND METHODS: We recruited 11 patients with pathologically proven DEC treated at our institute. We evaluated primary lesion size, location and signal intensity on MRI, and prognosis. MRI and pathological findings were compared in eight resected patients. RESULTS: Primary tumors ranged from 16 to 206 mm in diameter. DEC was located at the endometrium in 9 of the 11 patients; the remaining two patients showed diffuse involvement of the enlarged myometrium. These two patients with diffuse involvement type died within 4 months. Of the eight patients who underwent resection, seven had macroscopic intratumoral hemorrhage and six showed a high signal on T1-weighted images or low signal on T2-weighted images. Of the eight resected patients, four had tumor necrosis > 25% and tumor size > 5 cm. In these patients, necrosis appeared as nonenhanced areas on contrast-enhanced MRI. CONCLUSION: MRI findings of DEC showed two patterns: mass-forming type and diffuse myometrial type with poor prognosis. Most patients with DEC had intratumoral hemorrhage, and large tumors (> 5 cm) had gross necrosis, which appeared as nonenhanced areas on contrast-enhanced MRI.

Role of SMARCA4 (BRG1) and SMARCB1 (INI1) in Dedifferentiated Endometrial Carcinoma With Paradoxical Aberrant Expression of MMR in the Well-Differentiated Component: A Case Report and Review of the Literature.

INTRODUCTION: Dedifferentiated endometrial carcinoma is an uncommon highly aggressive uterine tumor. It comprises 2 components: a well-differentiated, low-grade epithelial carcinoma and an undifferentiated carcinoma. The undifferentiated carcinoma frequently exhibits rhabdoid cytologic features. Many of these tumors are characterized by an aberrant switch/sucrose non-fermenting (SWI/SNF) complex. They may also exhibit aberrant expression of mismatch repair (MMR) proteins. Together, these play an important role in the pathogenesis and aggressive nature of the tumor. MATERIAL AND METHODS: We present a case of dedifferentiated endometrial carcinoma in a 63-year-old female showing loss of expression of SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4/BRG1), and aberrant expression of MMR proteins. We also review the literature starting from the earliest recognition of this entity and the various studies done to explain its molecular pathogenesis and prognostic importance. RESULTS AND CONCLUSIONS: Recognition of SWI/SNF complex-deficient dedifferentiated endometrial carcinoma is important as these tumors do not respond to platinum-based chemotherapy, and consideration of alternative therapies is often necessary. We also want to emphasize that though most of the studies have found MMR deficiency in the undifferentiated carcinoma component, it may be seen only in the low-grade, well-differentiated component, as observed in this case.

Clinicopathological significance of multiple molecular features in undifferentiated and dedifferentiated endometrial carcinomas.

We investigated the clinicopathological significance of multiple molecular features in undifferentiated and dedifferentiated endometrial carcinomas (UDECs). Eighteen dedifferentiated endometrial carcinomas (DDECs) and three undifferentiated endometrial carcinomas (UECs) were collected. Polymerase-ε exonuclease domain mutations (POLE-EDM) were analysed by Sanger sequencing. SWI/SNF complex subunits, mismatch repair (MMR) proteins, p53, and PD-L1 were evaluated by immunohistochemistry. The SWI/SNF complex was inactivated in half of the UDECs; variably combined with deficient MMR (dMMR), POLE-EDM, or p53 aberrance. Deficiencies in BRG1 and ARID1A were mutually exclusive (p<0.05) in DDECs. ARID1A defects were mostly (8/9) associated with dMMR and typically occurred simultaneously in both endometrioid and dedifferentiated components, whereas BRG1 defects were less frequently (3/7) combined with dMMR and were only observed in dedifferentiated cells. Two-thirds of the UDECs displayed dMMR, mainly caused by the MLH1 promotor methylation. Mutant p53 immunostaining was detected in accordant or subclonal patterns. All three POLE-EDM UDEC patients had stage IA disease with either dMMR or p53 abnormality. Strong positive signals for PD-L1 were mainly detected in dMMR samples. BRG1 defects may likely trigger the progression of dedifferentiation in UDECs by superimposing the pre-existing driver events or by initiating UECs de novo, whereas ARID1A inactivation is subordinate and may likely be secondary to dMMR. The biological behaviours of BRG1-intact UDECs were evaluated according to The Cancer Genome Atlas molecular classification; their driver events require further analysis. Exact molecular subtypes can be helpful for clinical management and treatment decisions for patients with UDEC.

A report of two cases of dedifferentiated endometrioid carcinoma: A newly described underrecognized tumor of poor prognosis.

Dedifferentiated endometrioid carcinoma or dedifferentiated endometrioid adenocarcinoma (DEAC) is defined by the presence of undifferentiated carcinoma with endometrioid carcinoma. Undifferentiated component can be misinterpreted as solid component of high-grade endometrioid carcinoma or sarcomatous component of malignant mixed mullerian tumor. We present two cases of DEAC. Two postmenopausal women underwent hysterectomy for vaginal bleeding. Microscopically, sections from the endometrial tumors showed a biphasic growth consisting of an undifferentiated component and a glandular component with sharp transition between the two components. The undifferentiated component showed focal positivity for cytokeratin and vimentin, while glandular component was diffusely positive for cytokeratin and negative for vimentin expression.

SWI/SNF Complex Mutations in Gynecologic Cancers: Molecular Mechanisms and Models.

The SWI/SNF (mating type SWItch/Sucrose NonFermentable) chromatin remodeling complexes interact with histones and transcription factors to modulate chromatin structure and control gene expression. These evolutionarily conserved multisubunit protein complexes are involved in regulating many biological functions, such as differentiation and cell proliferation. Genomic studies have revealed frequent mutations of genes encoding multiple subunits of the SWI/SNF complexes in a wide spectrum of cancer types, including gynecologic cancers. These SWI/SNF mutations occur at different stages of tumor development and are restricted to unique histologic types of gynecologic cancers. Thus, SWI/SNF mutations have to function in the appropriate tissue and cell context to promote gynecologic cancer initiation and progression. In this review, we summarize the current knowledge of SWI/SNF mutations in the development of gynecologic cancers to provide insights into both molecular pathogenesis and possible treatment implications for these diseases.

Carcinoma dediferenciado do endométrio: Uma revisão da literatura / Dedifferentiated endometrial carcinoma: A literature review

"O Carcinoma Dediferenciado do Endométrio (DDEC) é uma neoplasia constituída por dois componentes histológicos morfologicamente distintos (diferenciado e indiferenciado). O componente diferenciado corresponde a um carcinoma endometrioide de baixo grau (I ou II), enquanto o componente indiferenciado é caracterizado por células epiteliais homogêneas de tamanho médio, sem qualquer tipo de diferenciação ou padrão morfológico arquitetural. Esta neoplasia foi descrita inicialmente em 2006, mas somente em 2014 foi incluída na classificação dos tumores da Organização Mundial de Saúde (OMS). Por ser uma entidade relativamente nova e ainda desconhecida por parte de alguns patologistas, estimase que o DDEC seja subdiagnosticado. O componente indiferenciado pode ser confundido com área sólida de um carcinoma endometrioide grau III ou mesmo com outras entidades tais como tumores neuroendócrinos, sarcomas ou linfomas. O estudo imuno-histoquímico e molecular contribui para confirmação do diagnóstico. Este trabalho tem como objetivo revisar a literatura recente do DDEC para melhor caracterização dos seus aspectos clínicopatológicos, já que esta neoplasia tem um pior prognóstico quando comparado com os carcinomas endometrioides e serosos uterinos."(AU)

"Dedifferentiated Endometrial Carcinoma (DDEC) is a neoplasm consisting of two morphologically distinct histological components (differentiated and undifferentiated). The differentiated component corresponds to a low grade endometrioid carcinoma (I or II), while the undifferentiated component is characterized by homogeneous epithelial cells of medium size, without any kind of differentiation or architectural morphological pattern. This neoplasm was first described in 2006, but only in 2014 it was included in the World Health Organization (WHO) classification of tumors. Because it is a relatively new entity and still unknown to some pathologists, it is estimated that DDEC is underdiagnosed. The undifferentiated component can be confused with the solid area of a grade III endometrioid carcinoma or even with other entities such as neuroendocrine tumors, sarcomas or lymphomas, and immunohistochemical and molecular study contribute to confirmation of the diagnosis. This paper aims to review the recent literature of DDEC to better characterize its clinical and pathological aspects, since this neoplasia has a worse prognosis when compared to endometrioid and serous uterine carcinomas"(AU)

Dedifferentiated Endometrial Carcinoma Could be A Target for Immune Checkpoint Inhibitors (Anti PD-1/PD-L1 Antibodies).

Dedifferentiated endometrial carcinoma (DDEC) is defined as an undifferentiated carcinoma admixed with differentiated endometrioid carcinoma (Grade 1 or 2). It has poor prognosis compared with Grade 3 endometrioid adenocarcinoma and is often associated with the loss of mismatch repair (MMR) proteins, which is seen in microsatellite instability (MSI)-type endometrial cancer. Recent studies have shown that the effectiveness of immune checkpoint inhibitor therapy is related to MMR deficiency; therefore, we analyzed the immunophenotype (MMR deficient and expression of PD-L1) of 17 DDEC cases. In the undifferentiated component, nine cases (53%) were deficient in MMR proteins and nine cases (53%) expressed PD-L1. PD-L1 expression was significantly associated with MMR deficiency (p = 0.026). In addition, the presence of tumor-infiltrating lymphocytes (CD8+) was significantly associated with MMR deficiency (p = 0.026). In contrast, none of the cases showed PD-L1 expression in the well-differentiated component. Our results show that DDEC could be a target for immune checkpoint inhibitors (anti PD-L1/PD-1 antibodies), especially in the undifferentiated component. As a treatment strategy for DDEC, conventional paclitaxel plus carboplatin and cisplatin plus doxorubicin therapies are effective for those with the well-differentiated component. However, by using immune checkpoint inhibitors in combination with other conventional treatments, it may be possible to control the undifferentiated component and improve prognosis.

Rapid progression of disease in two cases of undifferentiated endometrial carcinoma.

Undifferentiated endometrial carcinoma, a rare histopathologic diagnosis, has a poor prognosis with high risk of progression during or shortly after completion of adjuvant treatment. We present two cases of undifferentiated endometrial carcinoma: one in a postmenopausal female who experienced recurrent disease immediately after completion of adjuvant treatment and one in a premenopausal female who experienced disease progression while receiving adjuvant treatment. These cases exemplify the aggressive behavior of undifferentiated endometrial carcinoma and suggest the need for a more effective treatment in the upfront setting than the current standard of care for endometrioid endometrial adenocarcinoma.

Dedifferentiated endometrial carcinoma: an ongoing diagnostic dilemma.

Tumours of uterine corpus are the most common gynaecological malignancies. The clinicopathological features of most of these tumours are well understood; however, dedifferentiated endometrial carcinoma still requires a lot of research to establish adequate management guidelines. The entity was first described in 2006 and is an aggressive tumour with poor prognosis. We present two cases of this tumour with a literature review, emphasising morphologic and immunohistochemical features that may help in the differential diagnosis.

Dedifferentiated endometrial carcinoma: A report of three cases and review of the literature.

Dedifferentiated endometrial carcinoma, which is defined microscopically as the co-existence of undifferentiated carcinoma and grade 1 or 2 endometrioid adenocarcinoma, is an aggressive type of cancer regardless of the percentage of undifferentiated components. It is reported that undifferentiated carcinoma comprises 9% of endometrial carcinoma. The percentage of dedifferentiated endometrial carcinoma has been hypothesized to be 40% of undifferentiated carcinoma. A precise pathological diagnosis is essential for defining the appropriate therapeutic approach and prognosis. Furthermore, since there is an association between dedifferentiated endometrial carcinoma and Lynch syndrome, it is important to identify the patient's genetic background. The current case report presents three cases of dedifferentiated endometrial carcinoma treated in our hospital. In immunohistochemical staining for DNA mismatch-repair (MMR) proteins in dedifferentiated endometrial carcinoma, the components of undifferentiated carcinoma demonstrated a loss of MMR protein expression, and it is suspected that there may be a germline mutation in these cases. Therefore, Lynch syndrome should be suspected and the appropriate genetic approaches in cases of dedifferentiated endometrial carcinoma should be considered.