Endometrioid Endometrial Adenocarcinoma Research Articles

Validating the 2023 FIGO staging system: A nomogram for endometrioid endometrial cancer and adenocarcinoma.

To find the factors impacting overall survival (OS) prognosis in patients with endometrioid endometrial carcinoma (EEC) and adenocarcinoma and to establish a nomogram model to validate the 2023 International Federation of Obstetrics and Gynecology (FIGO) staging system for endometrial cancer. Data were obtained from the Surveillance, Epidemiology, and End Results (SEER) training cohort. An independent validation cohort was obtained from the First Affiliated Hospital of Anhui Medical University between 2008 and 2023. Cox regression analysis identified independent prognostic factors for OS in EEC and adenocarcinoma patients. A nomogram predicting OS was developed and validated utilizing the C-index, calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). The relationship between the tumor grade and prognosis of EEC and adenocarcinoma was quantified using net reclassification improvement (NRI), propensity score matching (PSM), and Kaplan-Meier curves. Cox regression analysis identified age, race, marital status, tumor grade, tumor stage, tumor size, and chemotherapy as independent prognostic factors for OS. A nomogram for predicting OS was developed based on these factors. The C-indexes for the OS nomogram was 0.743 and 0.720 for the SEER training set and external validation set, respectively. The area under the ROC (AUC) for the OS nomogram was 0.755, 0.757, and 0.741 for the SEER data subsets and 0.844, 0.719, and 0.743 for the external validation subsets. Calibration plots showed high concordance between the nomogram-predicted and observed OS. DCA also demonstrated the clinical utility of the OS nomogram. NRI, PSM, and survival analyses revealed that tumor grade was the most important histopathological factor for EEC and adenocarcinoma prognosis. Seven independent prognostic variables for the OS of patients with EEC and adenocarcinoma were identified. The established OS nomogram has good predictive ability and clinical utility and validates the 2023 endometrial cancer FIGO staging system.

The usefulness of p16 and COX-2 expression on the prediction of progression to endometrial cancer.

Endometrial cancer (EC) is the most commonly diagnosed gynecological cancer. Endometrial hyperplasia (EH) is a more common diagnosis than EC. Endometrial hyperplasia is found in approximately 1.5% of all women presenting with abnormal bleeding. Endometrial hyperplasia progresses to EC, and especially, cancer risk increases in cases with atypical hyperplasia. p16, one of the tumor suppressor proteins involved in the cell cycle, and COX-2, one of the key enzymes of prostaglandin synthesis, are important markers for the diagnosis of both EH and EC. There is lack of consensus in the classification, diagnosis and treatment of EH. The subject of changes in the cell cycle in the progression of endometrial pathologies may help to identify and prevent these affected pathways in the treatment stage. The aim of this study is to investigate the expression of p16 and COX-2 during the development of EC from EH. We investigated COX-2 and P16 expressions in patients with proliferative endometrium, complex/simple endometrial hyperplasia and endometrioid adenocarcinoma. p16 expression increased in EH and EC (p<0.001). COX-2 expression was increased in endometrial cancer compared to other groups, but this increase was not found to be statistically significant. Although p16 and COX-2 expression were increased in patients with advanced grade/stage, lymphovascular invasion, and >50% of myometrial invasion, this increase was not statistically significant. More detailed studies are needed to investigate the prognostic significance of the COX-2 molecule. COX-2 might be a potential biomarker for the prognosis of endometrial cancer and a potential therapeutic target for EC treatment. Also, it might be used to prevent the progression of precursor lesions to invasive EC.

Abstract LB215: Polymerase θ (POLθ) inhibitors (novobiocin, ART-558, RP6685) were tested with 22 approved and investigational agents in multi-cell type spheroids of genetically selected patient-derived human tumor cell lines

Abstract The potential of novobiocin to augment cancer chemotherapy was explored in the late 1980s and early 1990s in tumor cells and tumor-bearing mice and in Phase 1 clinical trials with cyclophosphamide or cisplatin. The molecular target of novobiocin was identified to be DNA POLθ which has a role in repair of DNA double strand breaks (DSB) during mitosis. Genetic alterations which may increase or decrease POLθ inhibitor effects have been elucidated. Thirty patient-derived tumor cell lines with known BRCA, ATM, ATR, POLQ, XRCC1, PALB2, PARP1, and LIG3 alterations were screened in a complex spheroid assay (tumor cells, endothelial cells, mesenchymal stem cells) with a POLθ inhibitor (novobiocin, ART-558, or RP6685), alone or in simultaneous combination with a FDA approved or investigational anticancer small molecule, using a 7-day exposure and a CellTiter-Glo 3D luminescence endpoint. As single agents, the POLθ inhibitors had little or no cytotoxicity. Potentiation of the topoisomerase II inhibitors doxorubicin (DOX) and etoposide by the POLθ inhibitors ART-558 or RP6685 was observed in spheroids grown from the serous endometrial adenocarcinoma 922993-354-T-J3, which has ATM and BRCA2 variants. The 379773-124-R-J2 endometrioid endometrial adenocarcinoma which harbors mutant POLθ demonstrated antagonism with ART-558 in combination with PARP inhibitors and less than additive to additive cytotoxicity in combination with DOX. Activity of the Chk1/2 inhibitor prexasertib was potentiated by either ART-558 or RP6685 in the 922993-354-T-J3 complex spheroids. The combination of POLθ inhibitor ART-558 and the Chk1/2 inhibitor prexasertib produced up to 1 log increase in cytotoxicity in the 922993-354-T-J3 complex spheroids. KRAS G12D inhibitor MRTX-133 cytotoxicity against 186277-243-T-J2 colon adenocarcinoma with the KRAS G12D variant was potentiated by either ART-558 or RP6685. Potential combinations to advance into in vivo studies will be presented. This project was funded in part with federal funds from the NCI, NIH, under contract no. HHSN261201500003I. Citation Format: Beverly A. Teicher, Thomas S. Dexheimer, Thomas Silvers, Nathan P. Coussens, J Paul Eder, James H. Doroshow. Polymerase θ (POLθ) inhibitors (novobiocin, ART-558, RP6685) were tested with 22 approved and investigational agents in multi-cell type spheroids of genetically selected patient-derived human tumor cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB215.

Novel FOXL2 Mutation in an Ovarian Adult Granulosa Cell Tumor: Report of a Case With Diagnostic and Clinicopathologic Implications.

Adult granulosa cell tumor, the most common malignant ovarian sex cord-stromal tumor, harbors the characteristic mutation c.402C>G (p.C134W) in the FOXL2 gene in ~90% to 95% of cases. To date, no other variants of FOXL2 mutations have been identified in these tumors. Here we report the first case of an adult granulosa cell tumor with a novel FOXL2 point mutation c.398C>T (p.A133V) presenting in a 64-year-old postmenopausal woman. The patient underwent total hysterectomy and bilateral salpingo-oophorectomy for atypical endometrial hyperplasia and gross examination revealed an incidental 3.2cm right ovarian mass with a solid, bright yellow, homogeneous cut surface. Microscopically, ~30% of the tumor showed a nested growth pattern composed of uniform tumor cells with oval nuclei and a moderate amount of pale cytoplasm, while the remaining areas consisted of a bland storiform fibromatous stroma. Reticulin stain demonstrated loss of the individual pericellular network within the nested areas, while the pericellular staining pattern was retained in the background stromal component. FOXL2 sequencing analysis was performed in both components and revealed a c.398C>T (p.A133V) mutation in the nested component, whereas wild-type FOXL2 sequence was identified in the fibromatous stroma. Sections from the uterus showed a low-grade endometrioid endometrial adenocarcinoma with superficial myometrial invasion. The patient underwent adjuvant vaginal cuff brachytherapy for the endometrial carcinoma and is alive and well at 8 months follow-up. This case illustrates that new FOXL2 mutations may be detected in ovarian sex cord-stromal tumors with increasing use of routine molecular testing, adding to the complexity of the pathologic diagnosis. In the right morphologic and clinical context, a FOXL2 mutation-even if it is different from the dominant hotspot mutation c.402C>G (p.C134W)-can support the diagnosis of adult granulosa cell tumor.

Endometrial Cancer in a Transgender Man with Prolonged Exogenous Testosterone Use.

Hormone therapy (HT) in transgender males requires monitoring. For amenorrheic transmasculine individuals on HT, episodes of abnormal vaginal bleeding should be assessed promptly. A 33-year-old transgender man on exogenous testosterone therapy for medical gender transition was found to have stage IV endometrioid endometrial adenocarcinoma. Surgical resection was performed for symptom control, and the patient was treated with palliative chemotherapy. The tumor was androgen receptor-negative, and, after a multidisciplinary discussion of the risks and benefits of continuing exogenous testosterone, testosterone therapy was restarted postoperatively. Long-term androgen use may have unknown implications for the development of malignancy, and treating reproductive organ cancer in transgender males may be complicated by the desire to continue androgen therapy.

Incidental findings during donor liver assessment: Single center experience

Intraoperative consultation of donor liver is an important part of transplant evaluation and determination of liver eligibility. In this study, we describe incidental pathologic findings discovered during the pretransplant evaluation of liver donors in our Institution from 1/2010 to 12/2022. During this 13-year period 369 intraoperative consultations from 262 liver donors were performed. Of those cases, incidental findings were identified in 22 cases (5.9 %) from 19 donors (7.3 %); two donors had more than one lesion. The median age of this subset of patients was 53 years (range: 18–70) and females predominated (63 %). Sixteen of the donors had abnormal findings in the liver: 6 bile duct hamartoma (BDH), 5 hyalinized nodule with Histoplasma capsulatum, 5 focal nodular hyperplasia (FNH), 2 bile duct adenomas (BDA), 1 biliary cyst and 1 hemangioma. One donor had both FNH and a BDH. One BDH and 1 BDA case was misdiagnosed as malignancy during the frozen section evaluation. Three donors had extrahepatic pathologies: a pancreatic tail schwannoma, a low-grade appendiceal mucinous neoplasm, and a lymph node with metastatic endometrial endometrioid adenocarcinoma. Of the 19 livers, the final organ disposition was available for 9: 6 were transplanted (67 %) and 3 were discarded (33 %). Two of the 3 discarded organs were misdiagnosed BDH and BDA cases, and one was incorrectly reported as having 90 % microvesicular steatosis during the frozen assessment. We present the clinicopathologic characteristics of liver donors with incidental findings during the pre-transplant evaluation which could lead to unwarranted graft dismissal if misdiagnosed. Additionally, incidental fungal infections can have implications for immunosuppressive therapy and the decision to use or reject the graft.

Expressions of HuR, Methyl-HuR and Phospho-HuR in Endometrial Endometrioid Adenocarcinoma Are Associated with Clinical Features.

HuR regulates cytoplasmic mRNA stability and translatability, with its expression correlating with adverse outcomes in various cancers. This study aimed to assess the prognostic value and pro-oncogenic properties of HuR and its post-translational isoforms methyl-HuR and phospho-HuR in endometrial adenocarcinoma. Examining 89 endometrioid adenocarcinomas, we analyzed the relationship between HuR nuclear or cytoplasmic immunostaining, tumor-cell proliferation, and patient survival. HuR cytoplasmic expression was significantly increased in grade 3 vs. grade 1 adenocarcinomas (p < 0.001), correlating with worse overall survival (OS) (p = 0.02). Methyl-HuR cytoplasmic expression significantly decreased in grade 3 vs. grade 1 adenocarcinomas (p < 0.001) and correlated with better OS (p = 0.002). Phospho-HuR nuclear expression significantly decreased in grade 3 vs. grade 1 adenocarcinomas (p < 0.001) and non-significantly correlated with increased OS (p = 0.06). Cytoplasmic HuR expression strongly correlated with proliferation markers MCM6 (rho = 0.59 and p < 0.001) and Ki67 (rho = 0.49 and p < 0.001). Conversely, these latter inversely correlated with cytoplasmic methyl-HuR and nuclear phospho-HuR. Cytoplasmic HuR expression is a poor prognosis marker in endometrioid endometrial adenocarcinoma, while cytoplasmic methyl-HuR and nuclear phosphoHuR expressions are markers of better prognosis. This study highlights HuR as a promising potential therapeutic target, especially in treatment-resistant tumors, though further research is needed to understand the mechanisms regulating HuR subcellular localization and post-translational modifications.

Two lncRNA signatures with cuproptosis as a novel prognostic model and clinicopathological value for endometrioid endometrial adenocarcinoma.

Cuproptosis may contribute to tumorigenesis. However, the predictive value and therapeutic significance of cuproptosis-related lncRNAs (CRLs) in endometrioid endometrial adenocarcinoma (EEA) remains unknown. We obtained RNA-seq data from TCGA database and searched the Literature to identify cuproptosis-related genes. Using machine learning models, we identified prognostic lncRNAs for cuproptosis. Immune properties and drug sensitivity were investigated based on these signatures. Further, a ceRNA network was constructed by bioinformatics and in vitro experiments were performed. We determined two cuproptosis-related signatures to build the prognostic model in EEA. Afterward, the risk scores of two cuproptosis-related signatures were associated with clinicopathological molecular typing and as independent prognostic factors for EEA. In addition, we observed significant differences in immune function, checkpoints, and CD8+ T lymphocyte infiltration between the two risk groups. Furthermore, chemotherapy drugs such as AKT inhibitors exhibited lower IC50 values in the high-risk group. We speculate that ACOXL-AS1 can be served as an endogenous 'sponge' to regulate the expression of MTF1 by miR-421. Through in vitro experiments, we preliminarily validated the ceRNA network relationship in the cellular model. In EEAs, this study proposed a broad molecular signature of CRLs are promising biomarkers for predicting clinical outcomes and therapeutic responses.

The pregnancy and oncology outcome of fertility-sparing management for synchronous primary neoplasm of endometrium and ovary

PurposeTo investigate the efficacy of fertility-preserving treatment for young women with synchronous primary neoplasm of endometrium and ovary.MethodsWe retrospectively reviewed eight patients with concurrent primary grade 1 presumed stage IA endometrioid endometrial adenocarcinoma (EEA) or endometrial atypical hyperplasia (EAH) and primary stage I ovarian tumors who underwent fertility-sparing treatment in the Obstetrics and Gynecology Hospital of Fudan University between April 2016 and December 2022.ResultsSynchronous endometrial and ovarian cancers (SEOC) accounted for 50% of these eight patients. The median age of patients was 30.5 years (range, 28–34 years). None of them received chemotherapy. The median treatment time was 4 months (range, 3–8 months). 87.5% (7/8) cases achieved complete response (CR), and the median time to CR was 3.8 months (range, 1.5–7.7 months). Among patients who got CR, none of them showed any signs of recurrence. Pregnancies and successful deliveries were achieved in 4 of 5 patients. Till September 2023, the median follow-up period was 50.5 months (range:15.2–85.2 months).ConclusionFertility-sparing treatment is feasible for highly selected patients with synchronous neoplasm of the endometrium and ovary, but strict screening and monitoring are mandatory. Though the results of our limited cases are encouraging, long follow-up and more clinical data are required. Enrolled patients must be fully informed of the risks during conservative treatment.

Detection and dissection of sentinel nodes in endometrial endometrioid cancer with indocyanine green using PinPoint laparoscopy: Analysis of the learning curve

ObjectiveEarly-stage endometrial endometrioid adenocarcinoma is managed through laparoscopic total hysterectomy with bilateral salpingo-oophorectomy and pelvic lymphadenectomy. Detection of positive nodes is rare, and lymphadenectomy may involve complications. Pelvic sentinel lymph node dissection can prevent complete dissection. Herein, we evaluated the learning curve of sentinel lymph node dissection using indocyanine green.Study design: All surgeries for endometrial endometrioid adenocarcinoma were performed laparoscopically with indocyanine green to detect sentinel nodes. The primary outcome was the ability to identify and resect sentinel lymph nodes on each side. The secondary outcome was correspondence between the frozen section histology of the nodes with the final histology. ResultsAmong 31 patients with endometrial endometrioid adenocarcinoma treated between October 2018 and August 2020, 29 who underwent laparoscopy using indocyanine green were enrolled. Complete lymphadenectomy was performed in 16 patients. Failure to recognize sentinel nodes on right and left sides occurred in 10.34% and 0% of cases, respectively. The median number of recognized and dissected sentinel nodes was 1 on both sides (range 0–5). One patient had a lymph node positive for malignancy on histology (3.45%) on both sides. There were 13 and 14 cases of negative frozen sections on the right and left sides, respectively, and 1 case of a positive frozen section with positive whole pelvic lymph nodes. ConclusionSentinel node dissection using indocyanine green in endometrial endometrioid adenocarcinoma has a distinct learning curve; however, it is practical and achievable for skilled surgeons.

Adenocarcinomas of the Gynecologic Tract Involving the Urinary Bladder: A Series of 16 Cases Potentially Mimicking Urothelial Malignancy.

There is limited literature describing gynecologic adenocarcinomas involving the urinary bladder and potential diagnostic pitfalls. To describe key features distinguishing metastatic (or extension of) gynecologic adenocarcinomas from urothelial carcinomas with glandular differentiation. Retrospective review of surgical pathology cases of gynecologic adenocarcinomas involving the bladder from 2 different institutions, retrieved from surgical pathology archives, was performed. Morphologic features were recorded, along with immunohistochemistry results when available. Electronic medical records were reviewed for clinical and radiographic information. Sixteen cases of gynecologic adenocarcinomas (9 endometrial endometrioid adenocarcinomas, 4 endometrial serous carcinomas, 2 high-grade tubo-ovarian serous carcinomas, and 1 cervical adenosquamous carcinoma) involving the bladder were identified. All included cases had mucosal involvement potentially mimicking primary bladder neoplasms, including 4 cases originally diagnosed as urinary carcinomas. Tumors expressed keratin 7 (12 of 13; 92%), PAX8 (11 of 12; 92%), estrogen receptor (11 of 15; 73%), p16 (8 of 11; 73%), progesterone receptor (8 of 14; 57%), GATA3 (5 of 12; 42%), and p63 (3 of 11; 27%); all tumors were negative for keratin 20 (0 of 12). Features supportive of Müllerian origin included prior history of gynecologic malignancy, lack of morphologic heterogeneity in nonendometrioid tumors, and immunophenotypic coexpression of PAX8 and estrogen receptor with absent GATA3. Potential pitfalls seen in a subset of cases included misleading radiologic and cystoscopic findings, replacement of the overlying urothelial mucosa by tumor mimicking precursor lesions, focal GATA3 and/or p63 positivity, and areas of squamous differentiation in tumors of endometrioid histology. A combination of clinical history, certain morphologic features, and proper selection of immunohistochemical stains is key for the correct diagnosis of secondary gynecologic adenocarcinomas involving the urinary bladder.

Whole-tumor apparent diffusion coefficient histogram analysis for preoperative risk stratification in endometrial endometrioid adenocarcinoma.

To investigate the application of whole-tumor apparent diffusion coefficient (ADC) histogram metrics for preoperative risk stratification in endometrial endometrioid adenocarcinoma (EEA). Preoperative MRI of 502 EEA patients were retrospectively analyzed. Whole tumor ADC histogram analysis was performed with regions of interest drawn on all tumor slices of diffusion-weighted imaging scans. Risk stratification was based on ESMO-ESTRO-ESP guidelines: low-, intermediate-, high-intermediate-, and high-risk. Univariable analysis was used to compare ADC histogram metrics (tumor volume, minADC, maxADC, and meanADC; 10th, 25th, 50th, 75th, and 90th percentiles of ADC [recorded as P10, P25, P50, P75, and P90 ADC, respectively]; skewness; and kurtosis) between different risk EEAs, and multivariable logistic regression analysis to determine the optimal metric or combined model for risk stratifications. Receiver operating characteristic curve analysis with the area under the curve (AUC) was used for diagnostic performance evaluation. A decreasing tendency in multiple ADC values was observed from the low- to high-intermediate-risk EEAs. The (low + intermediate)-risk EEAs and low-risk EEAs had significantly smaller tumor volumes and higher minADCs, meanADCs, P10, P25, P50, P75, and P90 ADCs than the (high-intermediate + high)-risk EEAs and non-low-risk EEAs (all P < 0.05), respectively. The combined models of the (meanADC + volume) and the (P75 ADC + volume) yielded the largest AUCs of 0.775 and 0.780 in identifying the (low + intermediate)- and the low-risk EEAs from the other EEAs, respectively. Whole-tumor ADC histogram metrics might be helpful for preoperatively identifying low- and (low + intermediate)-risk EEAs, facilitating personalized therapeutic planning.

The Added Value of ADC-based Nomogram in Assessing the Depth of Myometrial Invasion of Endometrial Endometrioid Adenocarcinoma

To explore the potential value of the apparent diffusion coefficient (ADC)-based nomogram models in preoperatively assessing the depth of myometrial invasion of endometrial endometrioid adenocarcinoma (EEA). Preoperative magnetic resonance imaging (MRI) of 210 EEA patients were retrospectively analyzed. ADC histogram metrics derive from the whole-tumor regions of interest. Univariate and multivariate analyses were used to screen the ADC histogram metrics and clinical characteristics for nomogram model building. The diagnostic sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) of two radiologists without and with the assistance of models were calculated and compared. Two nomogram models were developed for predicting no myometrial invasion (NMI) and deep myometrial invasion (DMI) with area under the curves of 0.85 and 0.82, respectively. With the assistance of models, the overall accuracies were significantly improved [radiologist_1, 73.3% vs 86.2% (p=0.001); radiologist_2, 80.0% vs 91.0% (p=0.002)]. In determining NMI, the sensitivity and PPV were greatly improved but not significant for radiologist_1 (51.9% vs 77.8% and 46.7% vs 75.0%, p=0.229 and 0.511), and under/near the significance level for radiologist_2 (59.3% vs 88.9% and 57.1% vs 82.8%, p=0.041 and 0.065), while the specificity, accuracy, and NPV were significantly improved (all p<0.001). In determining DMI, all sensitivity, specificity, accuracy, PPV, and NPV were significantly improved (all p<0.001). The ADC-based nomogram models can improve the diagnostic performance of radiologist in preoperatively assessing the depth of myometrial invasion and facilitate optimizing clinical individualized treatment decisions.

Combined deep-learning MRI-based radiomic models for preoperative risk classification of endometrial endometrioid adenocarcinoma.

Differences exist between high- and low-risk endometrial cancer (EC) in terms of whether lymph node dissection is performed. Factors such as tumor grade, myometrial invasion (MDI), and lymphovascular space invasion (LVSI) in the European Society for Medical Oncology (ESMO), European SocieTy for Radiotherapy & Oncology (ESTRO) and European Society of Gynaecological Oncology (ESGO) guidelines risk classification can often only be accurately assessed postoperatively. The aim of our study was to estimate the risk classification of patients with endometrial endometrioid adenocarcinoma before surgery and offer individualized treatment plans based on their risk classification. Clinical information and last preoperative pelvic magnetic resonance imaging (MRI) of patients with postoperative pathologically determined endometrial endometrioid adenocarcinoma were collected retrospectively. The region of interest (ROI) was subsequently plotted in T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), and diffusion-weighted imaging (DWI) MRI scans, and the traditional radiomics features and deep-learning image features were extracted. A final radiomics nomogram model integrating traditional radiomics features, deep learning image features, and clinical information was constructed to distinguish between low- and high-risk patients (based on the 2020 ESMO-ESGO-ESTRO guidelines). The efficacy of the model was evaluated in the training and validation sets of the model. We finally included 168 patients from January 1, 2020 to July 29, 2021, of which 95 patients in 2021 were classified as the training set and 73 patients in 2020 were classified as the validation set. In the training set, the area under the curve (AUC) of the radiomics nomogram was 0.923 (95%CI: 0.865-0.980) and in the validation set, the AUC of the radiomics nomogram was 0.842 (95%CI: 0.762-0.923). The nomogram had better predictions than both the traditional radiomics model and the deep-learning radiomics model. MRI-based radiomics models can be useful for preoperative risk classification of patients with endometrial endometrioid adenocarcinoma.

“Cheerios in the lung” as first metastases from endometrial endometrioid adenocarcinoma with adequate response to immunotherapy

BackgroundMetastases from endometrial carcinoma to the lungs are uncommon and cavitating metastases are even rarer. In some cases, lung cavitating metastases may resemble diffuse “Cheerios in the lung.”Case presentationA 58-year-old woman, smoker, with a history of hysteroannessiectomy and pelvic lymphadenectomy for a low stage endometrial endometrioid adenocarcinoma, came under our attention for dry cough without fever that persisted for over three months, and computed tomography (CT) revealed diffuse cavitating lung metastases resembling "Cheerios in the lung".After standard chemotherapy proved ineffective, Lenvatinib plus Pembrolizumab (immunotherapy) was administrated, leading to the disappearance of all lung nodules, leaving behind a diffuse emphysematous-like pattern.ConclusionsThis case is a rare example of metastatic endometrioid adenocarcinoma, manifested with chronic dry cough, with “Cheerios in the lung” appearence. The metastases responded well to immunotherapy, resulting in the regression of nodules into areas of diffuse emphysematous-like changes.

Independent Tissue-Based Biomarkers in Endometrioid Endometrial Cancer: Tumor Budding in Microsatellite Instability and WHO Grading in Copy-Number-Low Patients.

The molecular characterization of endometrial endometrioid adenocarcinomas has provided major advances in its prognostic stratification. However, risk assessment of microsatellite instability (MSI) and copy-number (CN)-low cases remains a challenge. Thus, we aimed to identify tissue-based morphologic biomarkers that might help in the prognostic stratification of these cases. Histomorphologic parameters (WHO grading, tumor budding (TB), tumor-stroma ratio (as a quantitative description of stromal desmoplasia), tumor-infiltrating lymphocytes (TIL), "microcystic, elongated, fragmented" (MELF) pattern) were analyzed in resection specimens of the TCGA-UCEC cohort (n = 228). For each quantitative parameter, a two-tiered system was developed utilizing systematically determined cutoffs. Associations with survival outcomes were calculated in univariate and multivariate analysis and validated in two independent cohorts. In MSI tumors, only TB remained an independent prognostic factor. TB (≥3 buds/high-power field) was associated with inferior outcomes and with lymph node metastases. The prognostic significance of TB was confirmed in two validation cohorts. For CN-low tumors, established grading defined by the WHO was independently prognostic with inferior outcomes for high-grade tumors. The evaluation of TB might help in identifying MSI-patients with unfavorable prognosis who, e.g., could benefit from lymphadenectomy. WHO-based grading facilitates independent prognostic stratification of CN-low endometrioid adenocarcinomas. Therefore, we propose the utilization of TB and WHO-based grading, two tissue-based and easy-to-assess biomarkers, in MSI/CN-low endometrial carcinomas for improved clinical management.

A phase II, randomized, double-blind study of the use of rucaparib vs placebo maintenance therapy in metastatic and recurrent endometrial cancer.

TPS5626 Background: There are currently no approved maintenance therapies for metastatic and recurrent endometrial cancer, which carries a dismal long-term prognosis. The PARP inhibitor drug class has demonstrated significant clinical benefit as a maintenance therapy for patients with germline/somatic BRCA mutations or homologous recombination deficiency (HRD) in ovarian cancers. However, BRCA mutations are not common in endometrial cancer. Loss of function of the tumor suppressor gene PTEN has been demonstrated in greater than 80% of endometrioid endometrial cancers 1. PTEN loss of function is well known to lead to activation of the PI3K-AKT-mTOR pathway but has also been shown to lead to defects in homologous recombination (HR) DNA repair of double strand breaks 2. Specifically, PTEN silencing leads to decreased RAD51 foci formation. Based on this mechanism, in vitro data on endometrial cancer cell lines has demonstrated sensitivity to PARP inhibitors. Notably, sensitivity of PARP inhibition in PTEN loss of function is independent of microsatellite instability (MSI) 3. Methods: This is a multi-center phase II, placebo controlled, double-blinded study of the use of rucaparib as maintenance therapy in patients with metastatic or recurrent endometrial cancer. A maximum of 138 patients will be randomized 1:1 to receive rucaparib at starting dose of 600mg BID dosing vs. placebo. Standard dose reductions of known toxicities will be followed based on FDA approved indications of rucaparib. Patients will remain on therapy until progression of disease or toxicity induced discontinuation. Eligible patients will have Stage III/IV or recurrent endometrial cancer and must have received one or two prior lines of chemotherapy. All histologic subtypes, including carcinosarcoma will be included. Treatment arms will be stratified on histology, number of lines of prior therapy, and complete vs partial response to prior line of therapy. The primary endpoint is progression free survival (PFS). Secondary endpoints include overall survival (OS), overall response rate (ORR), and toxicity. To date, 79 patients have been enrolled. 1. Mutter GL, Lin MC, Fitzgerald JT, et al. Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J Natl Cancer Inst. 2000;92(11):924-930. 2. Shen WH, Balajee AS, Wang J, et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell. 2007;128(1):157-170. 3. Dedes KJ, Wetterskog D, Mendes-Pereira AM, et al. PTEN deficiency in endometrioid endometrial adenocarcinomas predicts sensitivity to PARP inhibitors. Sci Transl Med. 2010;2(53):53ra75. Clinical trial information: NCT03617679 .

A Rare Case of Synchronous Uterine Leiomyosarcoma and Endometrial Endometrioid Adenocarcinoma

Assessment Synchronous primary neoplasms are defined when two or more neoplasms take place concurrently in the same patient. Concomitant endometrial adenocarcinoma and uterine leiomyosarcoma are extremely rare. Here we present an extremely rare case of uterine leiomyosarcoma coexisting with endometrial endometrioid adenocarcinoma of the uterus. A 52 years old woman was reported to a gynecology outpatient clinic with chief complaints lower abdominal pain, severe dysmenorrhea, and irregular vaginal bleeding for 7 months. Ultrasound of pelvis and abdomen showed a solitary intramural fibroid measuring 10x10cm. Surgery was planned and a simple total abdominal hysterectomy with bilateral salpingo-oophorectomy was performed and specimen was sent to the laboratory for examination. Histopathological examination from intramural mass showed high-grade leiomyosarcoma, spindle cell type with less than 50% of myometrial invasion. Sections from thickened endometrium showed endometrial endometrioid adenocarcinoma, FIGO grade I with an invasion of superficial fascicles of myometrium (&lt;50%). Morphological diagnosis was supported by Immunohistochemistry. Here we report an exceptionally rare case of synchronous uterine leiomyosarcoma and endometrial endometrioid adenocarcinoma. Our study may contribute to understand the prognosis of such multiple malignancies, common associations, and etiology of the disease so that a proper plan for further management of the patient can be implemented.

A new surgical approach for fertility-sparing management of diffuse endometrial G2 endometrioid adenocarcinoma: a step-by-step technique.

4% of endometrial cancers are diagnosed in young women and 70% are nulliparous. Preserve fertility in these patients is of major interest. It is demonstrated that hysteroscopic resection of focal well-differentiated endometrioid adenocarcinoma, followed by progestins achieve a complete response rate of 95.3%. Recently, fertility-sparing treatment was proposed also in case of moderately differentiated endometrioid tumors, with a relatively high remission rate. To show a new hysteroscopic approach, in case of fertility-sparing treatment of diffuse endometrial G2 endometrioid adenocarcinoma. Stepwise demonstration of the technique with narrated video footage for the fertility-sparing management of diffuse endometrial G2 endometrioid adenocarcinoma, combining the use of a 15 Fr bipolar miniresectoscope and 'three-steps' resection technique (Karl Storz, Tuttlingen, Germany) with a Tissue Removal Device (TRD) (Truclear Elite Mini, Medtronic). negative hysteroscopic assessment and endometrial biopsies at three and six months. Normal endometrial cavity and negative biopsies. Combined hysteroscopic technique, in case of diffuse endometrial G2 endometrioid adenocarcinoma, followed by double progestin therapy (Levonorgestrel releasing Intrauterine Device + Megestrole Acetate 160 mg/daily), may be associated with higher complete response rate; the use of TRD to complete the resection near tubal ostia may reduce risk of post-operative intrauterine adhesions and improve reproductive outcomes. A novel, fertility-sparing surgical approach for diffuse endometrial G2 endometroid adenocarcinoma.

The association of polypoid growth pattern with lymph node involvement in endometrioid type endometrial adenocarcinoma.

Tumor size is an independent predictor of lymph node metastasis and survival in the endometrioid type endometrial adenocarcinoma (EC). However, some of the ECs tend to grow towards the cavity in the polypoid pattern, which can reach very large sizes. In this study, we aimed to analyze the association of growing in the polypoid pattern of the tumor with the proportion of lymph node metastasis and extrauterine tumor spread. Four hundred seven patients were analyzed retrospectively. The effect of tumor size, tumor growing pattern, myometrial invasion, grade, and lymphovascular space invasion on the lymph node metastasis and extrauterine tumor spread were investigated. Statistical analysis consisted of unpaired t-tests for parametric data and Mann Whitney-U test for non-parametric data, whereas the Chi-square test for categorical variables. Logistic Regression, Cox Regression and multivariate analysis were used to estimate the risk predictors. No association was found between the growing in polypoid pattern and lymph node metastasis (P > 0.05). In the analysis of endometrioid type EC patients who had myometrial invasion less than ½ as a subgroup, no association was found between the growing pattern and lymph node metastasis and extrauterine disease. Tumor size was found to be a statistically significant predictor of lymph node metastasis and extrauterine disease (P < 0.05). Lymphovascular space invasion, grade, and myometrial invasion are associated with a higher proportion of lymph node metastasis. The polypoid growth pattern of the tumor does not correlate with any histopathological parameters.