Undifferentiated Endometrial Carcinoma Research Articles

SMARCA4 / BRG1 -deficient Uterine Neoplasm With Hybrid Adenosarcoma and Carcinoma Features: Expanding the Molecular-morphologic Spectrum of SMARCA4 -driven Gynecologic Malignancies.

SMARCA4 gene encodes BRG1 , a member of the SWItch/sucrose non-fermentable protein family involved in epigenetic transcriptional regulation of important cellular processes. In the uterine corpus, SMARCA4 / BRG1 deficiency is associated with a novel class of undifferentiated uterine sarcomas, characterized by younger age onset, rhabdoid histology, focal phyllodiform architecture, high-risk pathologic findings, and dismal prognosis. Herein, we report a case of a 34-year-old Asian woman with a SMARCA4 / BRG1 -deficient uterine tumor fulfilling the clinicopathologic features of an undifferentiated uterine sarcoma. However, the tumor exhibited several unique features that have not been previously emphasized, including (1) conspicuous phyllodiform architecture recapitulating conventional adenosarcoma, (2) rhabdoid tumor cells forming cords and keratin-positive cohesive epithelial islands, and (3) cooccurrence with a spatially distinct and discrete endometrial complex atypical hyperplasia from the rest of the proliferation. By immunohistochemistry, the tumor cells were diffusely positive for synaptophysin, whereas BRG1 was lost. Pertinent molecular findings included frameshift mutations in the SMARCA4 gene, mutations in histone modification and chromatin remodeling genes, including KMT2C , ARID1B , KAT6A , and NCOR1 , and mutations in Wnt signaling involving APC and CTNNB1 . Copy number gain in MDM2 and CDK4 were also identified. The tumor mutation burden was intermediate (6.8/MB) and it was microsatellite stable. On balance, our case exhibited morphologic and molecular features that overlap with (1) an undifferentiated uterine sarcoma, (2) an adenosarcoma with sarcomatous overgrowth, and (3) a mixed adenosarcoma and undifferentiated endometrial carcinoma. These hybrid features further expand the molecular-morphologic spectrum of SMARCA4 / BRG1 -deficient uterine neoplasms.

Dedifferentiated and Undifferentiated Ovarian Carcinoma: An Aggressive and Molecularly Distinct Ovarian Tumor Characterized by Frequent SWI/SNF Complex Inactivation

Dedifferentiated and undifferentiated ovarian carcinomas (DDOC/UDOC) are rare neoplasms defined by the presence of an undifferentiated carcinoma. In this study, we detailed the clinical, pathological, immunohistochemical, and molecular features of a series of DDOC/UDOC. We collected a multi-institutional cohort of 23 DDOC/UDOC and performed immunohistochemistry for core switch/sucrose nonfermentable (SWI/SNF) complex proteins (ARID1A, ARID1B, SMARCA4, and SMARCB1), mismatch repair (MMR) proteins, and p53. Array-based genome-wide DNA methylation and copy number variation analyses were performed on a subset of cases with comparison made to a previously reported cohort of undifferentiated endometrial carcinoma (UDEC), small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), and tubo-ovarian high-grade serous carcinoma (HGSC). The age of all 23 patients with DDOC/UDOC ranged between 22 and 71 years (with an average age of 50 years), and a majority of them presented with extraovarian disease (16/23). Clinical follow-up was available for 19 patients. Except for 2 patients, the remaining 17 patients died from disease, with rapid disease progression resulting in mortality within a year in stage II–IV settings (median disease-specific survival of 3 months). Eighteen of 22 cases with interpretable immunohistochemistry results showed loss of expression of core SWI/SNF protein(s) that are expected to result in SWI/SNF complex inactivation as 10 exhibited coloss of ARID1A and ARID1B, 7 loss of SMARCA4, and 1 loss of SMARCB1. Six of 23 cases were MMR-deficient. Two of 20 cases exhibited mutation-type p53 immunoreactivity. Methylation profiles showed coclustering of DDOC/UDOC with UDEC, which collectively were distinct from SCCOHT and HGSC. However, DDOC/UDOC showed an intermediate degree of copy number variation, which was slightly greater, compared with SCCOHT but much less compared with HGSC. Overall, DDOC/UDOC, like its endometrial counterpart, is highly aggressive and is characterized by frequent inactivation of core SWI/SNF complex proteins and MMR deficiency. Its molecular profile overlaps with UDEC while being distinct from SCCOHT and HGSC.

ARID1B Immunohistochemistry Is an Important Test for the Diagnosis of Dedifferentiated and Undifferentiated Gynecologic Malignancies.

Dedifferentiated and undifferentiated endometrial and ovarian carcinomas (DDC/UDC) are aggressive malignancies defined by morphologic and molecular undifferentiation, and associated with core SWI/SNF deficiency. Their main differential diagnoses include high-grade endometrial and ovarian carcinomas that often show overlapping morphologic and molecular profiles. Loss of cell lineage markers expression by immunohistochemistry (IHC) is commonly used to assist diagnosis, but it has poor specificity, while core SWI/SNF deficiency is much more specific. Approximately half of SWI/SNF-deficient DDC/UDC are associated with loss of ARID1B expression, yet, unlike the other core SWI/SNF proteins (SMARCA4 and SMARCB1), this test is rarely available, even in tertiary centers. Mutational testing for ARID1B is increasingly common among targeted DNA sequencing panels, but it is difficult to interpret in the absence of IHC results. Overall, the importance of including ARID1B IHC as part of the routine panel for undifferentiated gynecologic malignancies should be emphasized, especially as SWI/SNF inactivation is becoming a necessary biomarker for diagnostics, clinical management, and clinical trial enrollment.

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.

Expression of laminin-1 and matrix metalloproteinase-9 in benign and malignant endometrium.

Laminin-1 and matrix metalloproteinase (MMP)-9 may play roles in the progression from benign to malignant endometrium, so we aimed to investigate their levels of expression in these tissues. This case-control study was conducted at a tertiary care center between January 2014 and December 2016. Paraffin blocks of 50 specimens of benign endometrium with proliferative (n = 20), secretory (n = 11), and atrophic (n = 5) endometrium; simple endometrial hyperplasia without atypia (n = 12); and endometrial polyp (n = 2) histology and 49 specimens of malignant endometrium with endometrioid (n = 40), serous (n = 7), clear cell (n = 1), and undifferentiated (n = 1) types were immunostained with laminin-1 and MMP-9 antibodies and assessed for basement membrane continuity for laminin-1 and the percentage and intensity of MMP-9 expression in epithelial cytoplasm. : Laminin-1 continuity in the basement membrane was higher in benign (92%) compared to malignant (16.3%) endometrium (p < 0.0001) without any difference between the subgroups within each group (p > 0.05). All atrophic endometria and endometrial polyps and 23.5% of low grade endometrioid and none of the other endometrial cancers showed uninterrupted basement membrane staining with laminin-1. All cases in malignant endometrium expressed MMP-9 with either low or high immunoreactivity while none of the cases in benign endometrium showed a high staining with MMP-9 (p < 0.01). Proliferative and hyperplastic endometrium together with grade 1 endometrioid cancer expressed MMP-9 better than the atrophic endometrium (p < 0.05). The immunoreactivity with MMP-9 increased gradually from secretory to hyperplastic endometrium and serous carcinoma (p < 0.05). MMP-9 expression in all types of cancers except grade 1 endometrioid and clear cell compared to proliferative endometrium was significantly higher (p < 0.05) and increased from proliferative to grade 2 endometrioid, grade 3 endometrioid, serous and undifferentiated endometrial carcinoma. Gradual increments in MMP-9 expression and basement membrane laminin-1 discontinuity may indicate progression from normal to hyperplastic and to low- and high-grade cancerous endometrium.

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 8.0cm (range, 2.5-13.0cm). 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.

Undifferentiated Endometrial Carcinoma—Diagnostic and Therapeutic Challenges

Abstract Undifferentiated/dedifferentiated endometrial carcinoma is clinically highly aggressive, particularly when it is defined by inactivation of core SWI/SNF proteins (co-loss of ARID1B, loss of SMARCA4, or loss SMARCB1 expression). We report here the case of a 37-year-old woman who presented with menorrhagia and the subsequent pathologic and clinical workup showed an advanced-stage ARID1A/ARID1B-deficient mismatch repair–proficient undifferentiated endometrial carcinoma. Despite pelvic external beam radiation and platinum/taxane-based chemotherapy (4 of 6 planned cycles), the patient experienced disease progression with osseous metastasis to her left elbow and died of her disease 7 months after clinical presentation. This case highlights the diagnostic and treatment challenges associated with such undifferentiated/dedifferentiated cancer types of the endometrium.

Perspectives in Endometrial Pathology

When you feel life at crossroads, you need higher perspective view. —Toba Beta in My Ancestor Was an Ancient Astronaut After the publication of the integrated genomic characterization of endometrial carcinoma by The Cancer Genome Atlas project in 2013, the subclassification of endometrial carcinoma has gained much more attention than previously. Like in many other areas in our profession, we are at a crossroad where molecular information is changing diagnostic practice. In this issue of AJSP: Reviews & Reports, Drs Bosse and Köbel share their thoughts in 2 separate articles on how they envision the future with the added complexity of molecular information on top of standard anatomical pathology. Both agree on the value of molecular information and certain basic principles (eg, the defining nature of key oncogenic alterations such as POLE mutations or mismatch repair deficiency). However, they have different views of how to integrate molecular subtype information with standard histomorphology: with one approach being more integrated versus more stand-alone. Although standard histomorphology and molecular subtype strongly correlate, sometimes they contradict each other. At this point, someone, either the pathologist or the oncologist, has to adjudicate. This decision is not generalizable and is dependent on the context of the specific histomorphology and the specific molecular result, and who would be better posed to make that decision than a pathologist? Designation of an endometrial carcinoma to a specific category increasingly conveys prognostic, predictive, and germline information; accurate and reproducible diagnosis is mandatory. Integration of the traditional and molecular parameters is critical to ensure a relevant taxonomy of endometrial pathology with the ultimate goal of improving the outcomes in women's health. Drs Chapel and Park next provide a comprehensive contemporary review on mesonephric-like adenocarcinomas. Although various explanations of the etiology of this tumor type have been discussed, the authors state that endometrial mesonephric-like adenocarcinomas likely arise through mesonephric-type transdifferentiation from endometrioid carcinomas. They describe the morphological, immunohistochemical, and molecular features of this tumor type and give recommendations for the diagnostic approach. They provide cogent clinical reasons to warrant distinguishing this tumor type from endometrioid carcinomas. The entity of undifferentiated endometrial carcinoma and its related dedifferentiated carcinoma has gained substantial interest over the last years. Drs Y.-S. Lee and C.-H. Lee take us a step further by emphasizing the importance of key molecular alterations in the SWI/SNF (SWItch/sucrose non-fermentable) pathway as a defining feature for cases that are associated with a devastating clinical outcome. Again, ancillary molecular testing enables a more homogeneous diagnosis, which clarifies the poor response to standard therapy and calls for more research in experimental models to find new ways to treat patients with this molecularly defined entity. The synchronous involvement of the endometrium and ovary/fallopian tube by carcinoma is a regular diagnostic challenge. Drs Singh et al provide a new perspective by separately discussing this issue for serous and endometrioid histotypes. Although questions remain, systematically the authors list criteria and provide reporting strategies for different scenarios based on current understanding. Perhaps, the integration of molecular subtypes particularly for endometrioid histotypes can further aid in risk stratification of these patients. We are increasingly receiving requests from obstetrician-gynecologist for CD138 immunohistochemistry in the context of infertility. Dr S. Lee reviews the current data: although there is some indication that diagnosis and successful treatment of chronic endometritis may positively affect pregnancy outcome, a single randomized clinical trial did not confirm this. Yet, another trial is ongoing, which uses ≥5 CD138+ plasma cells per 10 mm2 as cutoff for chronic endometritis. But the results are pending. Until then, there is no indication for routine use of CD138 or other immunohistochemistry to detect plasma cells in the context of infertility and certainly not in others.

Advances in the clinicopathological research of undifferentiated and dedifferentiated endometrial carcinoma

去/未分化子宫内膜癌（undifferentiated and dedifferentiated endometrial carcinoma）是一组罕见的、组织形态相似、分子特征各异的高级别子宫内膜癌，目前被归为具有侵袭性生物学行为和不良预后的内膜癌组织亚型，临床治疗方案较为激进。迄今为止，组织学特征及免疫组织化学标志物仍是主要的诊断依据，但难以充分反映其分子机制的内部差异。本文总结了近年来关于去/未分化子宫内膜癌的病理诊断、分子机制及预后的相关研究进展，有助于临床病理医师对该疾病的深入了解及认识。.

ZEB1 expression is frequently detected in undifferentiated and de-differentiated carcinomas, but is not specific among endometrial carcinomas.

The pathological diagnosis of undifferentiated and de-differentiated endometrial carcinomas (UC/DCs) is prognostically important. However, undifferentiated components may be confused with other subtypes, particularly grade 3 endometrioid carcinomas (G3ECs). Zinc finger E-box binding homeobox 1 (ZEB1) has recently been identified as a promising marker because it is frequently expressed in the undifferentiated components of UC/DCs, but not in other carcinomas. Therefore, we herein evaluated the diagnostic utility of ZEB1 with an emphasis on distinguishing between UC/DCs and G3ECs using an expanded cohort of endometrial carcinomas and carcinosarcomas. Immunostaining for ZEB1 was performed on whole-tissue sections of 19 UC/DCs, 194 non-UC/DC endometrial carcinomas and 29 carcinosarcomas. Staining was defined as negative (< 5%), focal (5-50%) and diffuse expression (> 50%). ZEB1 was expressed in 84% of the undifferentiated components of UC/DCs (diffuse in 14, focal in two). Focal expression was observed in eight non-UC/DC endometrial carcinomas and diffuse expression in seven, with the latter comprising G3ECs (four of 76), serous carcinoma (one of 37), clear cell carcinoma (one of 21) and neuroendocrine carcinoma (one of three). Epithelial differentiation was morphologically and immunohistochemically less evident in G3ECs and neuroendocrine carcinoma with diffuse ZEB1 expression. All carcinosarcomas showed diffuse ZEB1 expression in their sarcomatous components. Immunostaining for ZEB1 was sufficiently sensitive to detect undifferentiated components. Diffuse ZEB1 expression showed high specificity for distinguishing between undifferentiated components and G3ECs; however, ZEB1 expression was not entirely specific to UC/DCs. The integration of ZEB1 into the diagnosis of UC/DCs requires careful examination to exclude other tumours, such as less differentiated G3ECs, neuroendocrine carcinomas and carcinosarcomas.

Endometrial neuroendocrine carcinoma and undifferentiated carcinoma are distinct entities with overlap in neuroendocrine marker expression.

Dedifferentiated endometrial carcinomas (DDECs)/undifferentiated endometrial carcinomas (UDECs) frequently harbour genomic activation of switch/sucrose non-fermentable (SWI/SNF)-complex proteins, and can show histological overlap with neuroendocrine carcinoma (NEC). The aim of this study was to compare the extent of the expression of neuroendocrine markers, SWI/SNF proteins and mismatch repair (MMR) proteins in DDEC/UDEC and NEC. The extent of expression of synaptophysin, chromogranin, CD56, ARID1A, ARID1B, SMARCA4, SMARCB1 and MMR proteins was evaluated by immunohistochemistry on 44 SWI/SNF-deficient DDECs/UDECs and 15 NECs. Thirty-three of 44 (75%) DDECs/UDECs showed expression of at least one neuroendocrine marker, with 18 of 44 (41%) expressing two or more neuroendocrine markers, whereas all 15 NECs showed expression of at least one neuroendocrine marker, with 14 of 15 (93%) expressing two or more neuroendocrine markers. Neuroendocrine marker expression in DDECs/UDECs was typically focal when present, with average extents of 17%, 4% and 8% for synaptophysin, chromogranin and CD56 in the positive cases, respectively, in contrast to 73%, 40% and 62% in the positive NEC cases, respectively. All 15 NECs showed intact expression of SWI/SNF-complex proteins, except for one that showed isolated loss of ARID1A. Thirty-eight of 44 DDECs/UDECs were MMR-abnormal (34 with loss of MLH1 and PMS2, and four with loss of PMS2 alone), whereas all NECs retained MMR protein expression. Our study demonstrates frequent but typically focal neuroendocrine marker expression in SWI/SNF-deficient DDECs/UDECs, whereas NECs typically express two or more neuroendocrine markers, with diffuse expression of at least one marker. ARID1B, SMARCA4 and SMARCB1 immunohistochemistry can be used to aid in the differentiation between DDEC/UDEC and NEC.

Cellular context determines DNA methylation profiles in SWI/SNF-deficient cancers of the gynecologic tract.

SWI/SNF (SWItch/Sucrose Non-Fermentable) complex deficiency has been reported in a wide variety of cancers and is often associated with an undifferentiated phenotype. In the gynecologic tract SWI/SNF-deficient cancers are diagnostically challenging and little is known about their cellular origins. Here we show that undifferentiated endometrial carcinoma (UDEC), SMARCA4-deficient uterine sarcoma (SDUS), and ovarian small cell carcinoma, hypercalcemic type (SCCOHT) harbor distinct DNA methylation signatures despite shared morphology and SWI/SNF inactivation. Our results indicate that the cellular context is an important determinant of the epigenetic landscape, even in the setting of core SWI/SNF deficiency, and therefore methylation profiling may represent a useful diagnostic tool in undifferentiated, SWI/SNF-deficient cancers. Furthermore, applying copy number analyses and group-wise differential methylation analyses including endometrioid endometrial carcinomas and extracranial malignant rhabdoid tumors, we uncover analogous molecular features in SDUS and SCCOHT in contrast to UDEC. These results suggest that SDUS and SCCOHT represent chromosomally stable SWI/SNF-deficient cancers of the gynecologic tract, which are within the broader spectrum of malignant rhabdoid tumors. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

The value of SOX2 in the differential diagnosis of SMARCA4 (BRG1)-deficient uterine neoplasms

SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4/BRG1)-deficient undifferentiated uterine sarcoma (SDUS) is a recently described uterine sarcoma. It is characterized by predominantly rhabdoid or large epithelioid cells with abundant cytoplasm and varying components of small and spindle cells, resembling the 'large cell variant' of small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). In addition, SMARCA4-inactivating mutations have been described as the driver mutations in SDUS. However, undifferentiated endometrial carcinoma (UDEC) and dedifferentiated endometrial carcinoma(DDEC) may show some clinical and morphological overlaps with SDUS, and about 20% of reported UDEC/DDEC cases also have loss expression of SMARCA4. SDUS is a very aggressive disease and universally lethal in all reported cases. Differentiating SDUS from UDEC/DDEC is relevant for the prognosis, pathogenesis, and possible targeted therapies for the disease. In this study, we compared the clinical, morphological, immunohistochemical, and molecular characteristics of 10 tumors including 2 SDUS, 2 SCCOHT, 1 uterine carcinoma with neuroendocrine differentiation (UDEC?), and 5 UDEC/DDEC. All 5 UDEC/DDEC cases showed strong and diffuse nuclear positivity for SOX2, while all SCCOHT and SDUS cases were completely negative. We concluded that SOX2 could be a useful marker for the differential diagnosis between SDUS and UDEC/DDEC.

Treatment and outcomes in undifferentiated and dedifferentiated endometrial carcinoma.

ObjectiveUndifferentiated and dedifferentiated endometrial carcinoma is a rare type of uterine malignancy. This study assesses disease characteristics, treatment and survival outcomes in patients with undifferentiated and dedifferentiated endometrial carcinoma treated at BC Cancer.MethodsAll patients diagnosed with undifferentiated and dedifferentiated endometrial carcinoma between 2000 and 2019 at BC Cancer were reviewed centrally. Clinical, pathologic, treatment and outcomes were reviewed retrospectively. The Kaplan-Meier method was used to evaluate overall survival (OS) and disease-free survival (DFS). Multivariable analysis was performed using Cox regression analysis.ResultsFifty-two patients were included, 33% had undifferentiated carcinoma and 67% dedifferentiated carcinoma. Sixty-nine percent of those who had mismatch repair (MMR) testing of their tumor had an abnormal profile. The 5-year DFS was 80% (95% confidence interval [CI]=71%–89%) for stage I/II, 29% (95% CI=28%–40%) for stage III and 10% (95% CI 1%–19%) for stage IV. The 5-year OS was 84% (95% CI=75%–92%) for stage I/II, 38% (95% CI=26%–50%) for stage III and 12% (95% CI=1%–24%) for stage IV. Multivariate analysis showed that receiving adjuvant chemotherapy, adjuvant radiotherapy, lower stage and better Eastern Cooperative Group performance status were associated with improved DFS (p<0.05).ConclusionPatients with stage I/II undifferentiated and dedifferentiated endometrial carcinoma had excellent survival outcomes, those with stage III/IV had worse outcomes, similar to previously reported. Adjuvant chemotherapy and radiotherapy were associated with improved DFS. MMR testing should be performed for these patients due to the high incidence of abnormal profiles.

Outcome of undifferentiated/dedifferentiated endometrial carcinoma in a single institution

Outcome of undifferentiated/dedifferentiated endometrial carcinoma in a single institution

Dedifferentiated endometrial carcinoma: molecular characteristics and clinical outcomes

<h3>Objectives:</h3> We sought to describe the molecular characteristics of each histological component of undifferentiated and dedifferentiated endometrial carcinomas, as well as the clinical outcomes of cases from a large single institution cohort. <h3>Methods:</h3> Endometrial carcinoma cases with diagnosis of undifferentiated or dedifferentiated carcinoma from 2014-2017 were included. Demographic and clinical data were abstracted from the medical record. Central pathologic review was performed by expert gynecologic pathologist, and cases were excluded if final diagnoses was not dedifferentiated or undifferentiated endometrial carcinoma. Slides from hysterectomy specimen were evaluated via IHC for MMR (mismatch repair)proteins (MLH1, PMS2, MSH2, MSH6), p53, and PD-L1. Sanger sequencing for TP53 and POLE and MSI genotyping were performed on tumor DNA for each case. <h3>Results:</h3> A total of 12 of 772 cases (1.6%) with a clinical diagnosis of dedifferentiated or undifferentiated endometrial carcinoma were evaluated. A total of 2 were excluded after central pathologic review (carcinosarcoma, FIGO grade 3 endometrioid). All remaining cases were classified as dedifferentiated carcinoma. Seventy percent of patients presented with advanced stage disease. The majority of patients were treated with multimodal adjuvant therapy, however 30% progressed rapidly prior to completing treatment. Of those who completed primary treatment, no recurrences were noted. Ninety percent of cases showed MMR protein loss and 8/9 had concordant MMR IHC findings in the histologic subtypes. No <i>TP53</i> or <i>POLE</i> mutations were identified on tumor sequencing. <h3>Conclusions:</h3> Concordant MMR protein loss between histologic subtypes of dedifferentiated endometrial carcinoma lends credence to the theory that the undifferentiated component arises from the low-grade endometriod component. The high rate of MMR protein observed in dedifferentiated tumors points to immunotherapy checkpoint inhibitors an attractive treatment option. The current study does not offer molecular characteristics that can adequately explain the dichotomies in outcomes seen in our patients. Further research to identify prognostic and predictive biomarkers will greatly aid in expanding our ability to make informed decisions regarding optimal management strategies.

Infrequent loss of SMARCA4, SMARCA2, and SMARCB1 expression in uterine mesenchymal tumors

SMARCA4-deficient uterine sarcoma (SMARCA4-DUS) was recently proposed as a new entity of uterine sarcoma. Reported cases of SMARCA4-DUS showed the loss of SMARCA4 and SMARCA2 expression. However, the prevalence of their deficiency in uterine mesenchymal tumors remains unclear. This study immunohistochemically examined the expression of SMARCA4, SMARCA2, and SMARCB1 in 206 uterine mesenchymal tumorsand detected a round cell tumor with the loss of SMARCA4 and SMARCA2 and a low-grade endometrial stromal sarcoma with SMARCA4 deficiency. The remaining 204 cases, including 170 smooth muscle tumors, 22 endometrial stomal nodule/sarcomas, seven undifferentiated uterine sarcomas, two adenosarcomas, one uterine tumor resembling ovarian sex cord tumor, and two perivascular epithelioid cell tumors, retained the expression of both SMARCA4 and SMARCA2. All tumors retained SMARCB1 expression. The round cell tumor with the loss of SMARCA4 and SMARCA2 was composed of diffuse small round cell growth with follicle-like spaces, which resembled small cell carcinoma of the ovary, hypercalcemic type. Immunohistochemically, the tumor showed the proficient expression of mismatch repair proteins and wild-type p53 expression, which favored SMARCA4-DUS; however, the tumor harbored the PIK3CA mutation, andthus, was reclassified as undifferentiated endometrial carcinoma. In conclusion, SMARCA4, SMARCA2, and SMARCB1 were rarely deficient in uterine mesenchymal tumors. SMARCA4 immunohistochemistry has potential in the diagnosis of SMARCA4-DUS with the exclusion of some tumors showing its deficiency, such as endometrial stromal sarcoma and undifferentiated carcinoma. Undifferentiated carcinoma may show an indistinguishable morphology and immunophenotype from SMARCA4-DUS, andthus, molecular analysis is required for their distinction in diagnostic practice.

Understanding the role of indoleamine-2,3-dioxygenase and stromal differentiation in rare subtype endometrial cancer.

Endometrial cancer (EC) is a disease with good and poor prognostic subtypes. Dedifferentiated endometrial carcinoma (DEC), undifferentiated endometrial carcinoma (UEC), and clear cell endometrial carcinoma (CEC) are rare high-grade tumors, associated with a poor prognosis and high pathologic stage. Many studies have been performed on the programmed death-ligand 1 (PD-L1) axis mainly focus on endometrioid adenocarcinomas and little research has been done on rare subtypes. The present body of work aims to evaluate the role of indoleamine-2,3-dioxygenase (IDO-1) and stromal differentiation (SD), their correlation with clinicopathologic features and overall survival. Here we found that positive IDO-1 expression in immune cells correlated with worse disease-free survival (p = 0.02), recurrence (p = 0.03), high pathologic tumor stage (p = 0.024), lymph node metastasis (p = 0.028), and myometrial invasion (p = 0.03). Our findings suggest IDO-1 to be relevant in both MMR intact and deficient tumors; however, >20% immune cell staining was restricted to MMR deficient cancers. For the stroma, immature, myxoid differentiation was found to correlate with worse disease-free survival (p = 0.04). We also found the correlation between IDO-1 expression and immature stroma. Looking forward, IDO-1 could be promising for immunotherapy and SD could be the answer to clinical heterogeneity.

SWI/SNF-deficiency defines highly aggressive undifferentiated endometrial carcinoma.

Dedifferentiated/undifferentiated endometrial carcinoma (DDEC/UEC) is an endometrial cancer characterized by the presence of histologically undifferentiated carcinoma. Genomic inactivation of core switch/sucrose nonfermentable (SWI/SNF) complex proteins was recently identified in approximately two‐thirds of DDEC/UEC. The aim of this study was to delineate the clinical behavior of SWI/SNF‐deficient DDEC/UEC in comparison to SWI/SNF‐intact DDEC/UEC. The study cohort consisted of 56 SWI/SNF‐deficient DDEC/UEC (2 POLE‐mutated), which showed either SMARCA4 (BRG1) loss, ARID1A/1B co‐loss, or SMARCB1 (INI1) loss in the undifferentiated tumor, and 26 SWI/SNF‐intact DDEC/UEC (4 POLE‐mutated). The average age at diagnosis was 61 years for patients with SWI/SNF‐deficient tumors and 64 years for SWI/SNF‐intact tumors. Mismatch repair (MMR) protein deficiency was seen in 66% of SWI/SNF‐deficient and 50% of SWI/SNF‐intact tumors. At initial presentation, 55% of patients with SWI/SNF‐deficient tumors had extrauterine disease spread in contrast to 38% of patients with SWI/SNF‐intact tumors. The 2‐year disease specific survival (DSS) for stages I and II disease was 65% for SWI/SNF deficient tumors relative to 100% for SWI/SNF‐intact tumors (p = 0.042). For patients with stages III and IV disease, the median survival was 4 months for SWI/SNF‐deficient tumors compared to 36 months for SWI/SNF‐intact tumors (p = 0.0003). All six patients with POLE‐mutated tumors, including one with stage IV SWI/SNF‐deficient tumor were alive with no evidence of disease. Among the patients with advanced stage SWI/SNF‐deficient tumors, 68% (21 of 31) received adjuvant or neoadjuvant chemotherapy (platinum/taxane‐based) and all except the patient with a POLE‐mutated tumor (20 of 21) experienced disease progression either during chemotherapy or within 4 months after its completion. These findings show that core SWI/SNF‐deficiency defines a highly aggressive group of undifferentiated cancer characterized by rapid disease progression that is refractory to conventional platinum/taxane‐based chemotherapy. This underscores the importance of accurate clinical recognition of this aggressive tumor and the need to consider alternative systemic therapy for these tumors.

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.