Endometrioid-type Endometrial Carcinoma Research Articles

Endometroid type endometrial cancer after surgery: unravelling the interplay of sleep, fatigue, and psychological well-being.

Endometrioid carcinoma, originating in the endometrium glandular cells, is often detected early and treated by surgery. However, post-treatment life quality remains poorly studied, explicitly focusing on sleep quality, fatigue, and depression. In this cross-sectional, observational study, 147 female patients with endometrioid-type endometrial carcinoma were evaluated using standardised tools-Pittsburgh Sleep Quality Index (PSQI), Fatigue Assessment Scale (FAS), and Beck Depression Inventory (BDI). Patients were categorised based on sleep quality and depression levels. The study employed correlation and regression analyses to examine the relationships among these variables. No correlations were found between sociodemographic or lifestyle variables and sleep quality, fatigue, or depression (P > 0.05). A strong correlation was identified between PSQI and FAS (r = 0.623; P < 0.001), PSQI and BDI (r = 0.291; P < 0.001), and FAS and BDI (r = 0.413; P < 0.001). Fatigue and tumour grade were potential predictors of poor sleep. Sleep quality and depression predicted fatigue, while only fatigue was a predictor for depression. Radiotherapy and external radiation rates were notably higher in the mild depression group. Our study suggests an imperative for integrated multi-disciplinary approaches that focus on medical and psychological aspects of patient care to enhance long-term well-being and quality of life.

Is Substantial Lymphovascular Space Invasion Prognostic in Patients With Pathologically Lymph Node-Negative Endometrial Cancer?

Lymphovascular space invasion (LVSI) predicts for higher rates of recurrence and increased mortality in endometrial cancer. Using 3-tier LVSI scoring, a PORTEC-1 and -2 trials analysis demonstrated that substantial LVSI was associated with worse locoregional (LR-DFS) and distant metastasis disease-free survival (DM-DFS), and these patients possibly benefited from external beam radiation therapy (EBRT). Furthermore, LVSI is a predictor for lymph node (LN) involvement, but the significance of substantial LVSI is unknown in patients with a pathologically negative LN assessment. We aimed to evaluate clinical outcomes of these patients in relation to the 3-tier LVSI scoring system. We performed a single-institutional retrospective review of patients with stage I endometrioid-type endometrial cancer who underwent surgical staging with pathologically negative LN evaluation from 2017 to 2019 with 3-tier LVSI scoring (none, focal, or substantial). Clinical outcomes (LR-DFS, DM-DFS, and overall survival) were analyzed using the Kaplan-Meier method. A total of 335 patients with pathologically LN-negative stage I endometrioid-type endometrial carcinoma were identified. Substantial LVSI was present in 17.6% of patients; 39.7% of patients received adjuvant vaginal brachytherapy and 6.9% of patients received EBRT. Adjuvant radiation treatment varied by LVSI status. In patients with focal LVSI, 81.0% received vaginal brachytherapy. Among patients with substantial LVSI, 57.9% received vaginal brachytherapy alone, and 31.6% of patients received EBRT. The 2-year LR-DFS rates were 92.5%, 98.0%, and 91.4% for no LVSI, focal LVSI, and substantial LVSI, respectively. The 2-year DM-DFS rates were 95.5%, 93.3%, and 93.8% for no LVSI, focal LVSI, and substantial LVSI, respectively. In our institutional study, patients with pathologically LN-negative stage I endometrial cancer with substantial LVSI had similar rates of LR-DFS and DM-DFS compared with patients with none or focal LVSI. These findings highlight the need for multi-institutional studies to validate the prognostic value of substantial LVSI in this patient population.

Analysis of prognostic factors in Grade 3 endometrioid type endometrial carcinoma.

To investigate the prognostic factors of patients with Grade 3 endometrioid endometrial cancer (G3EEC). This four-center, retrospective study included a total of 129 women with G3EEC. Demographic, clinicopathologic, and survival data were collected. Kaplan-Meier method was used for survival analysis. Predictors of outcome were analyzed using Cox proportional hazards models. Median age at the time of diagnosis was 63 (range 39-87) years and median follow up was 37 (range 6-126) months. For the entire cohort, the 5-year disease-free survival (DFS) and overall survival (OS) were 54.3% and 63.6%, respectively. The 5-year DFS rates for lymphovascular space invasion (LVSI) -positive and -negative patients were 41.6% and 88.3%, respectively (P< 0.001). The 5-year OS rates for LVSI-positive and -negative patients were 54.7% and 88.3%, respectively (P= 0.001). Positive LVSI status was identified as the independent prognostic factor for decreased DFS and OS (hazard ratio [HR] 5.5, 95% confidence interval [CI] 1.65-18.86; P= 0.006 versus HR 4.4, 95% CI 1.33-14.58; P= 0.013, respectively). LVSI seems to be an independent prognostic factor for decreased DFS and OS in G3EEC patients.

A population-based study of outcomes in adjuvant radiotherapy for stage II endometrial carcinoma

ObjectiveOur study aimed to analyze recurrence and survival outcomes in stage II endometrial cancer patients treated with adjuvant radiotherapy at CancerCare Manitoba, a Canadian provincial cancer program.MethodsThis retrospective population-based cohort...

The Percentage of Peripheral Eosinophils as a Sensitive Marker for Differentiating FIGO Grade in Endometrial Adenocarcinomas

Studies on eosinophils have mostly been directed to parasitic infections and allergic diseases, but the role of eosinophils in oncology has been largely ignored. Eosinophils are an important modulator of the immune response and components of the inflammatory process against the tumor. This study has been done to reveal the relationship between the data of 318 patients whose final pathology result was reported as a pure endometrioid type endometrial carcinoma (EC) and pre-operative peripheral blood eosinophil percentages.The data were analyzed in two groups as present/absent according to whether there are tumor metastases in the adnexes, lymph nodes, cervical stroma, and whether there is lymphovascular space invasion. FIGO grade was taken as basis in the evaluation of the tumor grade; Low-grade defines grade 1 or 2, and high-grade defines grade 3. The requirement for lymph node dissection was designed according to Mayo criteria. SPSS software program was used for statistical analysis.The mean percentage of eosinophils in high-grade patients was 2.75 ± 0.35, and it was statistically significantly higher than the mean percentage of eosinophils of 1.79 ± 0.09 found in low-grade patients (p= 0.013). In the ROC analysis, when the cut-off eosinophil percentage was taken as 1.95%, the sensitivity was calculated as 62% and specificity as 67% (p= 0.004).Eosinophil percentages which are a simple, easily accessible, and inexpensive method can be an important pre-operative predictive tool. Eosinophil percentages can be used in determining the need for surgical staging in EC.

Is Substantial Lymphovascular Space Invasion Prognostic for Clinical Outcomes in Type II Endometrial Cancer?

AimsSubstantial lymphovascular space invasion (LVSI) compared with none or focal LVSI is predictive of lymph node involvement and worse clinical outcomes in endometrioid-type endometrial carcinoma. We aimed to quantify the incidence of substantial LVSI in type II (clear cell and serous) endometrial cancer and correlate the extent of LVSI with clinical outcomes. Materials and methodsA retrospective review was conducted on type II endometrial cancer patients who underwent surgical management from July 2017 to December 2019 using the three-tier LVSI scoring system. Binary logistic regression and Cox regression were used to analyse predictors of lymph node involvement or survival outcomes, respectively. The Kaplan–Meier method and Log-rank test were used to analyse differences in locoregional disease-free survival (LR-DFS), distant metastasis disease-free survival (DM-DFS) and overall survival between patients with substantial versus none/focal LVSI. ResultsIn 79 patients with type II endometrial carcinoma, no LVSI, focal LVSI and substantial LVSI was present in 48.1%, 15.2% and 36.7% of patients, respectively. Lymph nodes were involved in 0.0% with no LVSI, 20.0% with focal LVSI and 60.0% with substantial LVSI (P < 0.001). The median follow-up was 22.2 months. In patients with none/focal versus substantial LVSI, the 2-year LR-DFS and DM-DFS rates were 91.5% versus 71.4% (P = 0.01) and 90.2% versus 63.8% (P = 0.005), respectively. On univariate analysis, myometrial invasion ≥50%, tumour size ≥3.6 cm, substantial versus none/focal LVSI, lymph node involvement and omission of adjuvant radiotherapy were significant predictors for worse LR-DFS and DM-DFS (P < 0.05). DiscussionSubstantial LVSI has a high incidence in type II pathology at our institution and predicts for lymph node involvement and worse clinical outcomes.

Genetic features of endometrioid-type endometrial carcinoma arising in uterine adenomyosis.

This study aimed to clarify the genetic features of endometrioid-type endometrial cancer arising in adenomyosis (EC-AIA) using targeted sequencing and immunohistochemistry (IHC) for both carcinoma and adjacent adenomyosis tissues. We identified three endometrioid-type EC-AIAs in 689 patients with endometrial cancer; two exhibited grade 3 endometrioid carcinoma. IHC revealed retained expression of PMS2, MSH6, ARID1A, and PAX2. Two of them showed diffuse strong p53 expression only in the carcinoma. PTEN expression was lost in carcinoma of only one of these cases. Carcinoma had many gene mutations than adjacent adenomyosis in all cases. KRAS and TP53 mutations were found in two of them. The other patient had mutations in KRAS, PIK3CA, and PPP2R1A. They were classified as two "p53-mutated" and one "non-specific molecular profile." These molecular alterations in endometrioid-type EC-AIA imply similar carcinogenesis to a subset of endometrial endometrioid carcinoma and might be used as targets of liquid biopsy after further validation.

The Impact of P53 and KI67 Expression in Endometrial Cancer and its Effect on Survival

OBJECTIVE: This study was conducted to evaluate the relationship of p53 and Ki67 expression with prognostic factors in patients who underwent surgery due to a diagnosis of endometrial cancer, and to evaluate their use as molecular markers that can help with survival prediction. STUDY DESIGN: This retrospective cohort study included patients who underwent surgery for endometrial cancer indication at the Gynecologic Oncology Clinic of the University of Health Sciences Tepecik Training and Research Hospital between 2011 and 2019, and whose p53 and Ki67 from the dissected material were pathologically studied and who underwent pelvic/paraaortic lymph dissection between the relevant dates. RESULTS: The study included 140 patients who met the inclusion criteria, 60% (n=84) of whom had endometrioid type endometrial carcinoma and 40% (n=56) had non-endometrioid type endometrial carcinoma. Estrogen and progesterone receptor positivity was significantly higher in the endometrioid type endometrial carcinoma group (p&lt;0.001 and p&lt;0.001, respectively). The non-endometrioid type endometrial carcinoma group had a high degree of positive staining (+3 and +4 staining) with p53 was 51.8%, while this rate was 11.9% in the endometrioid type endometrial carcinoma group. The non- endometrioid group also had a high degree of positive staining of Ki67 at 51.8%, whereas the endometrioid group had 25%. The total staining rate with p53 and Ki67 was significantly higher in the non-endometrioid type group (p&lt;0.001 and p=0.001, respectively). The mean survival duration was less than six months in cases with high degree positive p53 [57.4±2.7, (52.1-62.8) vs 51.9±5.9, (41.8-61.9)] and the mean survival duration was less than eight months in cases with high degree positive Ki67 [59.6±2.9, (53.8-65.4) vs 51.6±4.3, (43.2-60.1)]. CONCLUSION: p53 and Ki67 can be new markers for the prediction of prognosis and duration in endometrial cancer. The results of this study pave the way for new studies: however, randomized controlled prospective and multi-center studies are needed for immunohistochemical measures to be used as a parameter.

Prognostic impact of histological review of high-grade endometrial carcinomas in a large Danish cohort.

The aim of this study was to investigate the outcome of histological subtype review of high-grade endometrial carcinoma (EC) and its prognostic impact in a large well-documented Danish nationwide cohort. From the Danish Gynecological Cancer Database (DGCD) 2005-2012 cohort, we included 425 patients with an original diagnosis of high-grade EC, independent of histologic subtype. Of these, at least one hematoxylin and eosin (H&E)-stained slide from 396 cases (93.2%) was available for review. The histologic subtype was reviewed by specialized gynecopathologists blinded to the original diagnosis and clinical outcome. Interobserver variability between original and revised histologic subtypes was analyzed using simple Kappa statistics. Hazard ratios (HR), recurrence-free survival (RFS), and overall survival were calculated for original and revised subtypes, respectively. Overall histologic subtype agreement was moderate (kappa = 0.42) with the highest agreement for endometrioid-type EC (EEC; 75.5%) and serous-type EC (SEC; 63.8%). For clear cell carcinoma and un-/dedifferentiated EC, agreement was significantly lower: 30.1% and 33.3% respectively. Of the 396 reviewed cases, only two (0.5%) were re-classified as low-grade EEC upon revision. Interestingly, GR3 EEC had better RFS than SEC with stronger significance after revision (HR 2.36 (95% CI 1.43-3.89), p = 0.001), compared to original diagnosis (HR 1.74 (95% CI 1.07-2.81), p = 0.024). In conclusion, this study confirmed that pathology review results in substantial shift in histological subtype in high-grade EC. After review, a stronger prognostic benefit for GR3 EEC as compared to other histological subtypes was observed. This work supports maintaining a low threshold for pathology revision of high-grade EC in clinical practice.

Mmp-9 and Fascin-1 Expression in Endometrioid-Type Endometrial Carcinoma and Their Prognostic Value

Matrix metalloproteinases (MMP) and fascin-1 play roles in epithelial–mesenchymal transition and tumour invasion. This study was performed to investigate the relationships of fascin-1 and MMP-9 expression with prognostic parameters in endometrioid-type endometrial carcinoma (EEC). A total of 100 cases of EEC were included in the study. Tissues were stained with antibodies against fascin-1 and MMP-9. The relationships between the immunohistochemical findings and clinicopathological prognostic parameters of EEC were examined. Tumour diameter was significantly related to lymphovascular invasion, FIGO stage and FIGO grade (p 2 cm was associated with a poor prognosis. The staining score for fascin-1 was ≤ 5 in 81 cases and > 5 in 19 cases (p > 0.05), and that for MMP-9 was ≤ 5 in 39 cases and > 5 in 61 cases (p > 0.05). Neither fascin-1 nor MMP-9 expression was significantly related to any of the clinicopathological parameters examined. There were no significant relationships of fascin-1 and MMP-9 expression with the clinicopathological parameters of EEC. The results of this study suggested that these molecules do not contribute to the clinical behaviour of EECs. A tumour size > 2 cm is associated with a poor prognosis in EEC patients. To verify these results, more studies are needed with larger patient groups.

Abstract PR005: CD73 sequestering mutant β-catenin at the membrane explains recurrence in CTNNB1 mutant endometrial cancer

Abstract Somatic missense mutations in exon 3 of CTNNB1 are associated with significantly worse recurrence-free survival in patients with low grade, early stage endometrioid-type endometrial carcinoma (EEC). CTNNB1 encodes for β-catenin, an integral protein in Wnt signaling and core member of E-cadherin-catenin cell-cell adhesions. Although CTNNB1 mutation identifies patients at higher risk for recurrence, not all patients will recur. Nuclear expression of β-catenin protein in CTNNB1-mutated EEC is not robust as is normally seen in other CTNNB1-mutated cancers such as desmoid tumor and colon cancer. This suggests cancer-specific molecular mechanisms may regulate mutant β-catenin in EEC. Previously, we identified a cancer-specific role for CD73, a cell surface 5’nuclotidase, in EEC. CD73 is downregulated and its loss associates with poor survival. Notably, CD73 inhibits tumor progression by increasing the localization of wild-type β-catenin to the membrane. Through fractionation and co-immunoprecipitation studies, using a highly homologous (97.4% identical; 100% identical in exon 3 (UniPort)) Xenopus exon 3 CTNNB1 mutant expressed in HEC-1-A cells, and human tumor data we provide evidence that CD73 sequesters mutant β-catenin at the membrane with E-cadherin, subsequently limiting its nuclear translocation. EEC patients with CTNNB1 mutation and low CD73 expression have increased incidence of recurrence (n = 29). CD73 levels were not significantly different with clinical stage or lymphatic and vascular space invasion, suggesting that CD73 expression independently predicts disease recurrence in patients with CTNNB1 mutant tumors. CTNNB1 mutations in EEC rarely occur in the region of the β-catenin protein that binds to E-cadherin. Thus, mechanisms regulating the movement of wild-type β-catenin to the membrane would be expected to be able to localize mutant β-catenin to the membrane regardless of exon 3 mutation. Immunohistochemistry studies of CTNNB1 mutant tumors (n = 11) show a strong association between CD73 expression and β-catenin localization in cancer cells. Cancer cells expressing membrane CD73 largely express β-catenin at the membrane. Whereas, in cancer cells with CD73 loss or cytoplasmic CD73 expression, β-catenin nuclear staining is increased. While these data are preliminary, CD73 sequestering mutant β-catenin to the membrane suggests a molecular mechanism for why certain patients with CTNNB1 mutant tumors recur. Accordingly, CD73 may serve as a biomarker for identifying patients for more aggressive clinical management to prevent recurrence. Citation Format: Jessica L. Bowser, Katherine C. Kurnit, Luan H. Phan, Jerry B. Harvey, Jiping Feng, SuSu Xie, Andrew B. Gladden, Pierre D. McCrea, Russell R. Broaddus. CD73 sequestering mutant β-catenin at the membrane explains recurrence in CTNNB1 mutant endometrial cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PR005.

Clinical Significance of the MELF Pattern Myometrial Invasion in Low Grade Endometrioid Type Endometrial Carcinoma

Clinical Significance of the MELF Pattern Myometrial Invasion in Low Grade Endometrioid Type Endometrial Carcinoma

Expression of IL17A in endometrial carcinoma and effects of IL17A on biological behaviour in Ishikawa cells.

ObjectiveA growing body of evidence suggests chronic inflammation triggers the process of endometrial carcinogenesis. Interleukin (IL) 17A is an important proinflammatory factor involved in the tumour angiogenesis processes of many solid tumours. This study aimed to characterize the function of IL17A in endometrioid-type endometrial carcinoma.MethodsLevels of IL17A in human endometrial tissues were analysed by immunohistochemistry. In vitro proliferation and migration were analysed in Ishikawa cells treated with IL17A, using cell counting kit-8, wound healing and transwell assays. Western blots were used to analyse levels of oestrogen receptor (ER)α and ERβ proteins in Ishikawa cells treated with IL17A.ResultsIL17A levels were significantly higher in endometrial carcinoma tissues than in endometrial hyperplasic tissues. Significantly increased proliferation and migration was observed in Ishikawa cells treated with IL17A versus controls. Investigation of the molecular mechanism revealed that IL17A treatment upregulated the ERα/ERβ protein ratio in Ishikawa cells.ConclusionsIL17A may be an important proinflammatory factor involved in promoting endometrial carcinogenesis.

Abstract C002: Dysregulation of fatty acid metabolism by TP53 mutations underlies more aggressive endometrial cancers in African American women

Abstract In the United States, endometrial cancer is the fourth most common malignancy among women, with an estimated 61,380 new cases and 10,920 deaths in 2017 (1). The incidence is increasing more rapidly among African American (AfAm) women than other racial/ethnic groups (2), and the 5-year survival rate in AfAms is much lower than other racial/ethnic groups, including Caucasian Americans (CaAm) (62% vs. 84%) (3, 4). Endometrioid-type endometrial carcinoma (EEC) accounts for about 75% of all endometrial carcinomas. Many patients with early-stage and low-grade EEC can be cured by surgery alone, but for women who present with higher-grade advanced-stage EEC, more aggressive therapy is needed. Studies have shown a close gene/environment interaction in endometrial cancer development and progression (5-7); however, why AfAm women have a higher mortality rate and why their incidence of endometrial cancer is increasing more rapidly remain unknown. To address this issue, we analyzed gene mutation profiles in AfAm and CaAm women with EEC, using samples and genomic data from The Cancer Genome Atlas (TCGA) including 397 patients with EEC (284 CaAm, 67 AfAm, and 46 other races) (8). We found that tumor suppressor gene, TP53, was the top differentially mutated gene that occurred more frequently in AfAm patients with EEC. This is consistent with our recent publication that the TP53 tumor suppressor is more frequently mutated in AfAm patients compared to CaAm patients when several cancer types (e.g., lung, colorectal, bladder, prostate and breast cancer) were analyzed together (9). Moreover, survival analysis of TCGA patients with EEC showed that patients with TP53 mutations have generally poorer outcomes than those with wild-type TP53. Furthermore, our pathway analysis using the RNA sequencing (RNA-Seq) data from TCGA showed that fatty acid metabolism pathway is upregulated in AfAm patients with EEC compared to their CaAm counterparts. Further analysis showed that TP53 mutations are also associated with downregulation of AMP-activated protein kinase (AMPK) and activation of mTOR (mammalian target of rapamycin) pathways, which can lead to dysregulation of fatty acid metabolism and promotion of tumorigenesis (10). Furthermore, obesity is a significant risk factor for EC (11, 12), consistent with our TCGA data analysis showing that AfAm patients with EEC were more likely to be obese than CaAm patients (39.1 vs. 34.6, mean BMI indexes) and with our observation in a cohort of 247 patients, including 47 AfAm and 196 CaAm patients with EEC (35.5 vs. 33.6, mean BMI indexes) from the Precision Oncology Initiative (POI) at Wake Forest Baptist Cancer Center (WFBCC). Of note, inhibition of AMPK activity also leads to obesity and type 2 diabetes (13). Thus, differential TP53 mutations emerge as a major genetic factor that contributes to cancer health disparity. Citation Format: Farideh Mehraein-Ghomi, Liang Liu, Umit Topaloglu, Karen Winkfield, Michael Kelly, Boris Pasche, Wei Zhang. Dysregulation of fatty acid metabolism by TP53 mutations underlies more aggressive endometrial cancers in African American women [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C002.

Should endometrial biopsy under direct hysteroscopic visualization using the grasp technique become the new gold standard for the preoperative evaluation of the patient with endometrial cancer?

ObjectiveTo investigate the diagnostic accuracy of endometrial biopsy performed with hysteroscopic direct visualization using the “grasp technique” for the detection of endometrial carcinoma (EC) histology type and tumor grade. MethodsA cross-sectional study including the clinical and pathology records of patients with confirmed EC who underwent definitive surgery at University of Naples was performed. The preoperative diagnosis of endometrial tumor type and grade obtained using the hysteroscopy grasp technique was correlated with the final pathology specimens. Those results were compared to the diagnostic accuracy of the biopsies collected in a cohort of patients who underwent preoperative diagnostic hysteroscopy followed by blind endometrial biopsy using the Novak curette with subsequent surgical definitive treatment at University of Pisa. Statistical analysis was based on frequency data and diagnostic agreement of the pathology results. ResultsA total of 129 patients were included in the final analysis. An agreement rate of 104/106 (98.1%) for endometrioid type and 15/23 (65.2%) for non-endometrioid type was obtained between preoperative hysteroscopic grasp endometrial biopsy specimens and the final pathology with a coefficient k for G1, G2 and G3 tumors of 0.928, 0.925 and 0.974, respectively. When compared to 121 patients undergoing preoperative blind Novak endometrial biopsy, the hysteroscopic grasp technique was superior in agreement rates for tumor histotype [diagnostic accuracy (0.922 vs 0.890); K value (0.705 vs 0.642)] and grade when in presence of endometrioid type EC (K Cohen 0.354 for G1, 0.263 for G2 and 0.488 for G3). ConclusionsPreoperative hysteroscopic guided “grasp” endometrial biopsy provides a more accurate diagnosis of EC histology type and tumor grade when in presence of endometrioid type tumor compared to blind endometrial biopsy obtained using the Novak curette.

Tumor lymphocytic infiltration impacts recurrence in endometrioid-type endometrial carcinoma.

e15239 Background: Endometrial cancers that have mismatch repair deficiency are associated with higher numbers of tumor-associated lymphocytes, but the clinical significance of this observation is unknown. Our objective was to quantify CD3+ and CD8+ tumor lymphocytes of MMR intact (MMRi) and MMRd endometrioid-type endometrial carcinomas and determine if there was an association with survival. Methods: MMRd was defined as endometrial carcinomas with loss of MLH1 expression due to MLH1 gene methylation and determined by immunohistochemistry. MMRi was defined as positive expression of MLH1, MSH2, MSH6, and PMS2. This was followed by Aperio image-based quantification was used to assess CD3+ and CD8+ lymphocyte populations in different regions of the primary endometrial carcinomas, including tumor periphery (tumor-myometrial interface), tumor center (bounded on all sides by tumor), and tumor hotspot (area with highest number of lymphocytes). Recurrence-free survival was estimated using Kaplan Meier and Cox regression. Median follow up time was 44 months. Results: 180 patients with endometrial carcinoma were analyzed of which 132 were MMRi and 48MMRd. The MMRd group had significantly higher levels of CD3+ and CD8+ lymphocytes regardless of which tumor region was assessed (Figure 1a, P &lt; 0.001). Lymphocyte counts in both MMRd and MMRi groups had wide standard deviations such that there was some overlap in counts between the groups (Figure 1). Both MMRd and higher CD3+ counts were associated with worse recurrence-free survival. CD3+ quantification in the tumor periphery captured 21/23 recurrences (Figure 1b, HR = 8.04; 95% CI: 1.88 -34.31; p = 0.005); this included all of the MMRd cases that recurred and 7 MMRi cases with higher numbers of CD3+ lymphocytes that also recurred. Conclusions: MMRd endometrial cancers have increased numbers of CD3+ lymphocytic infiltrates within the primary tumor. Higher CD3+ infiltration is associated with greater risk of recurrence regardless of tumor location. In predicting tumor recurrence, lymphocytic counts performed better than assessment of MMR. Thus, quantification of CD3+ lymphocytes should be explored as a predictive biomarker.

Can TROP2 be used as a prognostic marker in endometrioid endometrial carcinoma?

Endometrioid-type endometrial carcinoma is the most common malignancy of the female genital tract in developed countries. The prognosis greatly depends on the grade and stage of the disease. In some patients, the disease recurs in a short time after the surgical/medical therapy. Hence, it is important to predict the patients who will have worse prognosis at the beginning, to choose the appropriate treatment; resuming the search of new prognostic markers. Therefore, our study aimed to detect trophoblast cell surface antigen 2 (TROP2) as a new prognostic marker. The patients who underwent a hysterectomy and diagnosed with endometrioid-type endometrial carcinoma were evaluated retrospectively and TROP2 immunostain was performed to their tumoral slides. We evaluated TROP2 expressions in 102 patients immunohistochemically who underwent hysterectomy with the diagnosis of endometrioid-type endometrial carcinoma histopathologically and correlated them with the other generally accepted prognostic parameters. The Kolmogorov-Smirnov test and Q-Q plot test were used to verify the normality of the distribution of continuous variables. The Chi-square/Fisher's exact tests were used for categorical variables. Analyses were performed with SPSS Statistics for Windows, Version 20. High overexpression of TROP2 was seen in larger, higher-grade, deeper-invasive tumors, tumors with vascular invasion, and pelvic-lymph-node metastasis. These results were statistically significant (P ≤ 0.05). Overexpression of TROP2 in endometrioid-type endometrial carcinoma seems to be a poor prognostic factor; it may be useful in determining the biologically more aggressive tumors before the treatment. This early determination is very important to choose the appropriate surgery, adjuvant-treatments, and follow-up.

Quantitative next-generation sequencing-based analysis indicates progressive accumulation of microsatellite instability between atypical hyperplasia/endometrial intraepithelial neoplasia and paired endometrioid endometrial carcinoma

Atypical hyperplasia/endometrial intraepithelial neoplasia is an accepted precursor to endometrioid-type endometrial carcinoma. Mismatch repair-deficient endometrial carcinomas are also known to be a biologically and clinically distinct subset of tumors. However, the development of microsatellite instability in endometrial carcinogenesis has not yet been evaluated by novel next-generation sequencing-based methods. We examined 17 mismatch repair-deficient endometrioid endometrial carcinomas and their paired atypical hyperplasia/endometrial intraepithelial neoplasia precursors using a next-generation sequencing panel with quantitative microsatellite instability detection at 336 loci. Findings were compared to histological features, polymerase chain reaction-based microsatellite instability testing, immunohistochemical expression of mismatch repair proteins, and tumor mutational burden calculations. All 17 endometrial carcinomas and 8/17 atypical hyperplasia/endometrial intraepithelial neoplasia showed microsatellite instability by next-generation sequencing-based testing. Endometrial carcinoma specimens showed significantly more unstable microsatellite loci than paired atypical hyperplasia/endometrial intraepithelial neoplasia (mean: 40.0% vs 19.9 unstable loci, respectively). Out of nine microsatellite-stable atypical hyperplasia/endometrial intraepithelial neoplasia specimens, four showed mismatch repair loss by immunohistochemistry. All atypical hyperplasia/endometrial intraepithelial neoplasia and endometrial carcinoma specimens with microsatellite instability were also mismatch repair-deficient by immunohistochemistry. Tumor mutational burden was significantly greater in endometrial carcinoma than in paired atypical hyperplasia/endometrial intraepithelial neoplasia specimens, and tumor mutational burden was significantly correlated with percent unstable microsatellite loci. Paired atypical hyperplasia/endometrial intraepithelial neoplasia and endometrial carcinoma specimens show progressive accumulation of unstable microsatellite loci following loss of mismatch repair protein expression. Comprehensive next-generation sequencing-based testing of endometrial carcinomas offers new insights into endometrial carcinogenesis and opportunities for improved tumor surveillance, diagnosis, and management.

Identification of a subset of microsatellite-stable endometrial carcinoma with high PD-L1 and CD8+ lymphocytes

Immune checkpoint blockade has emerged as an effective therapeutic strategy for patients with advanced cancer. Identification of biomarkers associated with treatment efficacy will help to select patients more likely to respond to this approach. High levels of microsatellite instability, tumor expression of PD-L1, high tumor mutation burden, and increased tumor-infiltrating lymphocytes have all been associated with response to checkpoint inhibitor blockade. The purpose of this study was to determine if a subset of microsatellite-stable endometrioid endometrial carcinomas have higher immune cell infiltrates and/or expression of PD-L1. PD-L1 expression and characterization of immune cell infiltrates were analyzed in 132 microsatellite stable, FIGO grade 2 endometrioid carcinomas. PD-L1 was positive in 48% (63/132) of the tumors. Tumor cell expression of PD-L1 was significantly associated with lymphatic/vascular invasion and deep myometrial invasion. PD-L1 expression was especially prominent at the invasive front and in foci of tumor-associated squamous metaplasia. Twenty-one cases (16% of the total) with more diffuse and/or especially strong PD-L1 expression were identified. This PD-L1 high subset was associated with significantly higher numbers of tumor-associated CD3+ and CD8+ lymphocytes. Only one tumor in the PD-L1 high subset harbored a POLE mutation. PTEN immunohistochemical loss, a common event in endometrioid-type endometrial carcinoma and associated with local immune suppression in melanoma, was not associated with PD-L1 expression or lymphocyte/macrophage infiltration of the tumor. These results suggest that a subset of microsatellite-stable endometrial cancers has higher expression of PD-L1 and increased tumor-associated CD3+ and CD8+ lymphocytes, characteristics more commonly associated with endometrial cancers with high levels of microsatellite instability. These results suggest that screening strategies to select only microsatellite instability-high advanced endometrial cancers for checkpoint inhibitor therapy might exclude patients who could potentially benefit from this therapeutic approach.

RRBP1 overexpression is associated with progression and prognosis in endometrial endometrioid adenocarcinoma

BackgroundCurrently, ribosome-binding protein 1 (RRBP1) is considered to be a novel oncogene that is overexpressed in colorectal cancer, lung cancer, mammary cancer, esophageal cancer and other carcinomas. However, the relationship between RRBP1 and endometrioid-type endometrial carcinoma (EC) remains unknown. Our purpose is to explore the function of RRBP1 in endometrioid-type endometrial carcinoma.MethodsWe investigated the expression of RRBP1 protein by immunohistochemistry on paraffin-embedded surgical specimens from one hundred thirty patients with endometrioid-type endometrial carcinoma. We also evaluated the differences in RRBP1 expression between endometrial cancer samples (n = 35) and normal endometrial tissues (n = 19) by western blotting.ResultsRRBP1 was more highly expressed in endometrial cancer samples than in normal samples (P < 0.05). High levels of expression of RRBP1 were strongly correlated with pathological features, such as the Federation of Gynecology and Obstetrics (FIGO) stage, histological grade, depth of myometrial invasion and lymph node metastasis (P < 0.05). Furthermore, RRBP1 expression was an independent prognostic factor for overall survival (OS) and disease-free survival (DFS) in patients with EC (both P < 0.05).ConclusionThis experiment identifies the utility of RRBP1 in predicting EC prognosis, revealing that it may be a potential target for therapeutics of EC.