Endometrioid Endometrial Carcinoma Research Articles

Application of molecular classification to guiding fertility-sparing therapy for patients with endometrial cancer or endometrial intraepithelial neoplasia.

The aim of this study was to evaluate whether molecular classification was associated with treatment response in women with endometrial endometrioid carcinoma (EEC) or Endometrial atypical hyperplasia/endometrial intraepithelial neoplasia (EAH/EIN) treated with progestin. A retrospective analysis of 59 patients with EEC or EAH/EIN who received fertility-sparing therapy between 2013 and 2021 was performed. For each patient, medical records and pathological reports were reviewed. The treatment efficacy and tumor prognosis were evaluated. Immunohistochemistry analysis for p53 and MSH2, MSH6, PSM2, MLH1 were performed. Molecular classification was analyzed using a 11-gene panel based on next generation sequencing technology. 23 of 39 patients with EEC received complete response (CR) after fertility-sparing treatment which was significantly lower than the EAH/EIN group (58.97% vs 80.0%, P<0.05). Molecular classification via the Cancer Genome Atlas (TCGA) algorithm was successfully applied to 59 cases. The distribution of specimens into the four molecular classes was as follows: 83.05% (49/59) CNL(copy number-low)，6.78% (4/59) MSI-H (microsatellite instability -high), 5.08%(3/59) POLE-mutated and 5.08% (3/59) CNH(copy number-high). MSI and TP53 sequencing results were concordant with immunohistochemistry analyses of MMR and p53 protein. The patients with CNH and MSI-H subtypes showed worse prognosis than those with POLE-mutated and CNL subtypes. Molecular classification of EAH/EIN prior to management with progestin treatment was feasible and may predict patients at risk of progression.

PTEN Immunoexpression in Atypical Endometrial Hyperplasia and Endometrioid Endometrial Carcinoma: A Research Protocol

Introduction: One of the major cancers affecting women is of Endometrial Carcinoma (EC). Therefore, its molecular characterisation remains important. Phosphatase and Tensin Homolog (PTEN) gene defects are one such molecular pathology commonly seen in lesion of atypical endometrial hyperplasia and EC. However, studies on PTEN immunoexpression in India are scarce. Aim: To study immunoexpression of PTEN and its correlation with various clinicopathologic parameters in lesion of atypical endometrial hyperplasia and EC. Materials and Methods: It will be carried out as a crosssectional study with prospective and retrospective design with sample size of 20 cases each in two groups- cases diagnosed on biopsy or surgical specimen of atypical endometrial hyperplasia and endometrioid endometrial carcinoma type -1, dividing them into sample size of 20 for each group. PTEN immunoexpression will be observed by immunohistochemical method on paraffin section of the tissue. The study would make the observation on the PTEN positivity by IHC in atypical endometrial hyperplasia and type-1 EC. The positive research of IHC will be compared for various other clinicopathologic parameters included in the study for both the endometrial lesion. The statistics of comparison will be drawn by using standard statistical test.

Prognostic factors of adult granulosa cell tumors of the ovary: a Turkish retrospective multicenter study.

To define the clinical, histopathological features and the prognostic factors affecting survival in patients with adult granulosa cell tumors of the ovary (AGCT). A 322 patients whose final pathologic outcome was AGCT treated at nine tertiary oncology centers between 1988 and 2021 participated in the study. The mean age of the patients was 51.3±11.8 years and ranged from 21 to 82 years. According to the International Federation of Gynecology and Obstetrics 2014, 250 (77.6%) patients were stage I, 24 (7.5%) patients were stage II, 20 (6.2%) patients were stage III, and 3 (7.8%) were stage IV. Lymphadenectomy was added to the surgical procedure in 210 (65.2%) patients. Lymph node involvement was noted in seven (3.3%) patients. Peritoneal cytology was positive in 19 (5.9%) patients, and 13 (4%) had metastases in the omentum. Of 285 patients who underwent hysterectomy, 19 (6.7%) had complex hyperplasia with atypia/endometrial intraepithelial neoplasia, and 8 (2.8%) had grade 1 endometrioid endometrial carcinoma. It was found that 93 (28.9%) patients in the study group received adjuvant treatment. Bleomycin, etoposide, cisplatin was the most commonly used chemotherapy protocol. The median follow-up time of the study group was 41 months (range, 1-276 months). It was noted that 34 (10.6%) patients relapsed during this period, and 9 (2.8%) patients died because of the disease. The entire cohort had a 5-year disease-free survival (DFS) of 86% and a 5-year disease-specific survival of 98%. Recurrences were observed only in the pelvis in 13 patients and the extra-abdominal region in 7 patients. The recurrence rate increased 6.168-fold in patients with positive peritoneal cytology (95% confidence interval [CI]=1.914-19.878; p=0.002), 3.755-fold in stage II-IV (95% CI=1.275-11.063; p=0.016), and 2.517-fold in postmenopausal women (95% CI=1.017-6.233; p=0.046) increased. In this study, lymph node involvement was detected in 3.3% of patients with AGCT. Therefore, it was concluded that lymphadenectomy can be avoided in primary surgical treatment. Positive peritoneal cytology, stage, and menopausal status were independent prognostic predictors of DFS.

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.

Diagnostic Accuracy of Alpha-Methylacyl-CoA Racemase Immunohistochemical Expression for the Diagnosis of Ovarian and Endometrial Clear Cell Carcinomas

Background & Objective: Clear cell carcinoma (CCC) is an uncommon histopathologic subtype of ovarian and endometrial carcinoma. Due to the morphologic overlapping with other subtypes of ovarian and endometrial carcinomas, an accurate diagnosis is crucial.Methods: In this study, 31 cases of ovarian clear cell carcinoma (OCCC), 28 endometrial clear cell carcinoma (ECCC), and 80 non-CCC subtypes (33 high-grade serous carcinomas of the ovary, 2 low-grade serous carcinomas, 10 ovarian endometrioid, 3 serous carcinomas and 29 endometrioid carcinomas of the endometrium) were investigated for immunohistochemical expression of AMACR. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for the distinction of OCCC and ECCC from other histopathologic subtypes were calculated.Results: Positive AMACR staining was seen in 18 OCCCs (58%) and 10 ECCCs (35.7%). In the non-clear cell group, 44 cases of ovarian (98%) and 25 cases of endometrial carcinoma (78%) showed negative results. Only one case of ovarian endometrioid carcinoma and 7 cases (22%) of endometrial endometrioid carcinomas revealed a positive reaction (P<0.05). Collectively, sensitivity, specificity, PPV, and NPV of AMACR expression, for the diagnosis of OCCC were calculated as 58%, 98%, 94.7%, and 77.2%, respectively. The sensitivity, specificity, PPV, and NPV were shown to be as 35.7%, 78.1%, 58.8%, and 58.1%, respectively in the endometrium.Conclusion: AMACR may be a highly specific immunohistochemical marker for the distinction of serous and clear cell carcinoma. A small percentage of endometrioid carcinoma may show positive staining. The sensitivity of this marker may not be higher than the other well-known Napsin-A IHC marker.

Corded and hyalinized endometrioid endometrial carcinoma with high-grade features: a clinicopathological and TCGA-based molecular analysis.

Corded and hyalinized endometrioid carcinoma (CHEC) typically shows low-grade features and "no specific molecular profile" (NSMP). This study aimed to perform a clinicopathological and molecular characterization of endometrial CHEC with high-grade features. Immunohistochemistry for cytokeratin AE1/AE3, e-cadherin, β-catenin, estrogen receptor, progesterone receptor, p53, p16, and mismatch repair proteins was performed. A next-generation sequencing kit was used to assess POLE, POLD1, APC, MLH1, MSH2, MSH6, PMS2, MUTYH, EPCAM, and CTNNB1. Molecular groups, i.e., POLE-mutant, mismatch repair deficient (MMRd), p53-abnormal, and NSMP, were assigned according to the TCGA classifier. Six high-grade endometrial CHECs were identified. The mean age was 57.5years; 5/6 cases were uterine-confined. Five cases showed a diffusely and markedly atypical corded component and a MMRd or p53-abnormal signature; additional features included single-cell keratinization, necrosis, osteoid or myxoid/chondro-myxoid matrix, foci of anaplasia, and nuclear β-catenin expression. The remaining case showed a low mitotic count and a NSMP phenotype, with focal bizarre cells in an otherwise classical CH endometrioid carcinoma. All cases showed variably reduced expression of epithelial markers and hormone receptors in the corded component. No mutations were found in any of the analyzed genes. In conclusion, high-grade CHECs are a heterogeneous subset of biphasic endometrial carcinoma which show similarities and differences with classical CHEC and carcinosarcoma. These cases often show MMRd or p53-abnormal signatures.

Development of a novel predictive model for lymph node metastasis in patients with endometrial endometrioid carcinoma

BackgroundGlobally, the burden of endometrial endometrioid carcinoma (EEC) increases annually. However, the histological grade of EEC remains unelucidated. We developed a novel model for predicting lymph node metastasis (LNM) in patients with endometrioid carcinoma (EC), which has not been well established.MethodsA total of 344 patients with EEC were classified into training (n = 226) and validation (n = 118) cohorts. To develop a nomogram to predict LNM, independent predictors were defined using univariate and multivariate regression analyses. The calibration curve, area under the decision curve analysis (DCA), and receiver operating characteristic curve were used to evaluate the performance of the nomogram.ResultsIndependent predictors of LNM in EC were identified in the univariate analysis, including mitosis; microcystic, elongated, and fragmented patterns; lymphovascular invasion (LVI); necrosis; and high-grade pattern. Mitosis, LVI, and high-grade pattern remained independent predictors of LNM in multivariate analysis. An LNM nomogram that was constructed by incorporating the five predictors showed reliable discrimination and calibration. DCA showed that the LNM nomogram scoring system had significant clinical application value. In addition, a high nomogram score (score > 150) was a significant prognosticator for survival in both LNM-positive and LNM-negative ECs.ConclusionsOur novel predictive model for LNM in patients with EC has the potential to assist surgeons in making optimal treatment decisions.

Use of clinicopathological factors to predict prognosis of fertility-sparing treatment for endometrial endometrioid carcinoma and atypical hyperplasia.

The incidence of endometrial endometrioid carcinoma (EEC) has been gradually increasing over the past decade. Fertility-sparing therapy with progestin is a treatment option for EEC or endometrial atypical hyperplasia (AH). The present study evaluated the role of numerous prognostic factors following fertility-sparing therapy for EEC or AH. Furthermore, the present study assessed the strength of various clinicopathological indicators for the prediction of treatment efficacy. A retrospective analysis was performed of patients with EEC and AH who received fertility-sparing therapy between August 2013 and September 2021 at Peking University People's Hospital (Beijing, China). Endometrial specimens were obtained from each patient after 3 months of treatment and at the end of the fertility-sparing therapy, before treatment efficacy and prognosis were evaluated using the χ2 test. Furthermore, the protein expression levels of EEC biomarkers, such as estrogen receptor (ER), progesterone receptor (PR), paired box 2 (PAX2), PTEN and p53 were assessed using immunohistochemistry. The overall complete response (CR) rate of fertility-sparing treatment in the EEC group was 67.39% (31/46), whereas that in the AH group was 86.49% (32/37). The difference between the CR rates in the EEC and AH groups was statistically significant (P<0.05). There was no association between prognosis after treatment and ER, PAX2, PTEN or Ki-67 expression in the initially untreated AH or EEC groups. However, tissues with >50% positive PR expression were demonstrated to have a higher CR rate compared with those with ≤50% positive PR expression in both the EEC and AH groups. Furthermore, the PAX2-positive group tended to demonstrate higher CR rates compared with the PAX2-negative group in the patients with EEC. In conclusion, these data suggested that fertility-sparing therapy is effective for patients with EEC and AH who wish to remain fertile after treatment. Specifically, in the AH group, a higher proportion of patients achieved a CR whilst also achieving this more rapidly. Furthermore, PR was demonstrated to be a useful marker for the evaluation of EEC and AH.

Oxidative stress-induced FAK activation contributes to uterine serous carcinoma aggressiveness.

Uterine serous carcinoma (USC) is an aggressive form of endometrial cancer (EC), characterized by its high propensity for metastases. In fact, while endometrioid endometrial carcinoma (EEC), which accounts for 85% of EC, presents a good prognosis, USC is the most frequently fatal. Herein, we used for the first time a peptide-based tyrosine-kinase-activity profiling approach to quantify the changes in tyrosine kinase activation between USC and EEC. Among the tyrosine kinases highly activated in USC, we identified focal adhesion kinase (FAK). We conducted mechanistic studies using cellular models. In a USC cell line, targeting FAK either by inhibitors PF-573228 and defactinib (VS-6063) or by gene silencing limits 3D cell growth and reduces cell migration. Moreover, results from our studies suggest that oxidative stress is increased in USC tumors compared to EEC ones. Reactive oxygen species (ROS) induce tyrosine phosphorylation of FAK and a concomitant tyrosine phosphorylation of paxillin, a mediator of FAK signal transduction. Mechanistically, by tracking hundreds of individual cells per condition, we show that ROS increased cell distance and migration velocity, highlighting the role of ROS-FAK-PAX signaling in cell migration. Both defactinib and ROS scavenger N-acetylcysteine (NAC) revert this effect, pointing toward ROS as potential culprits for the increase in USC cell motility. A proof of concept of the role of FAK in controlling cell growth was obtained in in vivo experiments using cancer-tissue-originated spheroids (CTOS) and a patient-derived orthotopic xenograft model (orthoxenograft/PDOX). Defactinib reduces cell proliferation and protein oxidation, supporting a pro-tumoral antioxidant role of FAK, whereas antioxidant NAC reverts FAK inhibitor effects. Overall, our data points to ROS-mediated FAK activation in USC as being responsible for the poor prognosis of this tumor type and emphasize the potential of FAK inhibition for USC treatment.

Surgical treatment of endometrioid endometrial carcinoma - laparotomy versus laparoscopy

Recent publications have raised doubts about the oncological safety of a laparoscopic approach in the treatment of endometrial cancer. The aim of this study was to investigate the beneficial aspects of laparoscopy versus laparotomy in patients with endometrial cancer, and present oncological outcomes. A retrospective study of patients who underwent surgery for the treatment of endometrioid endometrial cancer was performed. Surgical outcomes and complications in patients who were treated by laparoscopy or open surgery were compared. The patients were followed for 5-years. Patients’ characteristics, tumor stage, complications rate and oncologic outcome were analyzed. A total of 151 patients were included. The laparoscopy (n=80) and laparotomy (n=71) groups were homogeneous in regards of demographic data and tumor stage. Median average blood loss (1.31 vs. 1.92 g/dL), the mean duration of hospitalization (5.73 vs. 12.25 days), intraoperative (0 vs. 6%), and severe postoperative complications (5.1 vs. 14.3%) were significantly lower in the laparoscopy group. The numbers of pelvic or para-aortic lymph nodes removed during systematic lymphadenectomy were similar in both groups. Women who underwent laparoscopy and those who underwent laparotomy had similar five-year recurrence-free survival rates (88.7% vs. 91.5%, p=0.864), as well as similar overall five-year survival rates (91.2% vs. 97.2%, p=0.094). The oncological outcome of laparoscopy was similar to that of laparotomy in the treatment of patients with endometrial cancer. However, surgical outcomes and morbidity rates were significantly better in patients treated by laparoscopy. Clinical trials are essential to evaluate the oncological efficacy of laparoscopy in patients with endometrial cancer.

An assessment of mismatch repair deficiency in ovarian tumours at a public hospital in Johannesburg, South Africa

&#x0D; &#x0D; &#x0D; &#x0D; Background. Epithelial ovarian carcinomas (EOCs) are lethal female genital tract malignancies with high-grade serous, low-grade serous, endometrioid, clear cell, mucinous and malignant Brenner subtypes. The lifetime risk for developing ovarian carcinoma (OC) is 15% in females who have mismatch repair deficiency (MMR-d). MMR-d is associated with Lynch syndrome, a cancer predisposition condition. Patients who have MMR-d may benefit from immunotherapy. To the best of the authors’ knowledge, MMR-d testing of OCs in South Africa (SA) has not been undertaken to date.&#x0D; Objectives. To assess the clinicopathological characteristics and mismatch repair (MMR) status of non-serous EOCs at a single institution in SA.Methods. Following ethical clearance and application of exclusion criteria, 19 cases of non-serous EOC from the Department of Anatomical Pathology at Charlotte Maxeke Johannesburg Academic Hospital were retrieved and assessed. Four immunohistochemical markers (MLH1, MSH2, MSH6 and PMS2) were used to evaluate MMR status.&#x0D; Results. Most tumours were early-stage, unilateral, mucinous EOCs, without capsular breach or lymphovascular invasion (LVI). A single case of grade 1, stage I, unilateral, endometrioid EOC showed MMR-d for MLH1 and PMS2 MMR proteins. This patient had been diagnosed with endometrioid endometrial carcinoma 2 years prior to the diagnosis of OC.Conclusion. Our study documented a lower proportion of MMR-d OCs compared with international studies. However, our results are concordant with global studies regarding tumour subtype, laterality, grade, stage, LVI and capsular breach. Larger studies are required to estimate the true incidence of MMR-d OCs in SA and to direct effective treatment options globally.&#x0D; &#x0D; &#x0D; &#x0D;

Correlative Assessment of p53 Immunostaining Patterns and TP53 Mutation Status by Next-Generation Sequencing in High-Grade Endometrial Carcinomas.

TP53 mutations are frequently identified in the copy number-high molecular subgroup of endometrial carcinomas (ECs). P53 immunohistochemistry (IHC) is a widely used surrogate marker reflecting the mutational status of TP53 , and recent reports have shown ~95% concordance between the two methods in ECs. While these results are promising, studies evaluating the correlation between different p53 IHC staining patterns and comprehensive next-generation sequencing results are still limited. We compared the p53 IHC staining patterns, scored as wild-type, diffuse nuclear overexpression, null/complete absence, and cytoplasmic, to next-generation sequencing results reported by FoundationOneCDx in 43 high-grade ECs: 20 serous ECs, 9 mixed ECs with a serous component, 4 carcinosarcomas with a serous component, and 10 grade 3 endometrioid ECs. The concordance of p53 IHC and TP53 mutation status was 100% (43/43) overall, including 100% (33/33) concordance in tumors with a serous component and 100% (10/10) in endometrioid ECs. Among the 35 tumors with aberrant p53 expression the most commonly observed pattern was diffuse nuclear overexpression seen in 69% (24/35), followed by cytoplasmic staining in 17% (6/35), and complete absence of staining (null) in 14% (5/35) of tumors. Of the 6 tumors with cytoplasmic staining, 4 corresponded to missense mutations within the DNA binding domain (V157F in 2 tumors, and S127P and R280S, in 2 tumor each), while 2 corresponded to nonsense mutations in the tetramerization domain (p.E339*). Our results further support that p53 IHC can serve as an accurate predictor of TP53 alterations in ECs to aid the molecular-based tumor classification and the distinction between tumor histotypes, both of which play an important role in the assessment of clinical prognosis and therapeutic decision making. In addition, our data suggest, that the type and position of TP53 mutation may not directly correlate with the observed p53 IHC pattern in all tumors, and that there may be alternative mechanisms for cytoplasmic localization (other than mutations involving the nuclear localization domain), possibly due to conformational changes or posttranslational modifications of the aberrant p53 protein.

HE4 Tissue Expression as A Putative Prognostic Marker in Low-Risk/Low-Grade Endometrioid Endometrial Cancer: A Review.

Low-grade stage I endometrioid endometrial carcinomas should have an excellent prognosis, but a small subset of these cancers can relapse. The search for putative immunohistochemical prognostic markers for relapse in low-risk/low-grade endometrioid endometrial cancers remains open. Among the candidate molecules that may implicate the roles of immunohistochemical risk markers, we focused our attention on human epididymis protein 4 (HE4) after a review of the literature. Few authors have devoted themselves to this topic, and none have found a correlation between the tissue expression of HE4 and the molecular classification of endometrial cancer. Five different variants of HE4 mRNA and multiple protein isoforms of HE4 were identified many years ago, but current HE4 assays only measure the total HE4 expression and do not distinguish the different proteins encoded by different mRNA variants. It is important to have an approach to distinguish specific variants in the future.

The clinicopathological characteristics of POLE-mutated/ultramutated endometrial carcinoma and prognostic value of POLE status: a meta-analysis based on 49 articles incorporating 12,120 patients

ObjectiveThis study was designed to investigate the frequency and clinicopathological characteristics of POLE-mutated/ultramutated (POLEmut) in endometrial carcinoma (EC) and assess the prognostic values of POLE status.MethodsElectronic databases were screened to identify relevant studies. Meta-analysis was used to yield the pooled frequency of POLEmut and prognostic parameters by 95% confidence interval (CI), odd ratio (OR), and hazard ratio (HR).ResultsTotally, 12,120 EC patients from 49 studies were included. The pooled frequency of POLEmut was 7.95% (95% CI: 6.52–9.51%) in EC, 7.95% (95% CI: 6.55–9.46%) in endometrioid endometrial carcinoma, and 4.45% (95% CI: 2.63–6.61%) in nonendometrioid endometrial carcinoma. A higher expression occurred in grade 3 (OR = 0.51, 95% CI: 0.36–0.73, P = 0.0002), FIGO stage I-II (OR = 1.91, 95% CI: 1.29–2.83, P = 0.0013), and myometrial invasion< 50% (OR = 0.66, 95% CI: 0.50–0.86, P = 0.0025). Survival analyses revealed favorable OS (HR = 0.68, 95% CI: 0.55–0.85, P = 0.0008), PFS (HR = 0.74, 95% CI: 0.59–0.93, P = 0.0085), DSS (HR = 0.61, 95% CI: 0.44–0.83, P = 0.0016), and RFS (HR = 0.47, 95% CI: 0.35–0.61, P < 0.0001) for POLEmut ECs. Additionally, the clinical outcomes of POLEmut group were the best, but those of p53-abnormal/mutated (p53abn) group were the worst, while those of microsatellite-instable (MSI)/hypermutated group and p53-wild-type (p53wt) group were medium.ConclusionsThe POLEmut emergered higher expression in ECs with grade 3, FIGO stage I-II, and myometrial invasion< 50%; it might serve as a highly favorable prognostic marker in EC; the clinical outcomes of POLEmut group were the best one among the four molecular subtypes.

Microcystic, elongated and fragmented (MELF) pattern in endometrial carcinoma: clinicopathologic analysis and prognostic implications.

To assess the clinical value of microcystic, elongated, and fragmented (MELF) pattern in Chinese patients with endometrial endometrioid carcinoma. A total of 189 patients with endometrial endometrioid carcinoma were retrospectively analyzed in Peking University Third Hospital from January 2017 to December 2019. We analyzed the association of MELF pattern with the histopathologic data and prognosis of the patients, while immunohistochemistry was performed. The frequency of MELF pattern was 17.99% (34/189). MELF pattern was associated significantly with tumor size, myometrial invasion, histological grade, International Federation of Gynecology and Obstetrics stages, lymphovascular space invasion, and lymph node metastasis. According to multivariate logistic regression analysis, lymphovascular space invasion [95% confidence interval 1.021-48.485, P = .048] was a significant predictor of lymph node involvement. However, MELF pattern was not a significant predictor (95% confidence interval 0.054-2.279, P = .400). Loss of expression for mismatch repair proteins was observed in 10 MELF + cases (29.41%) and 54 MELF- cases (34.84%), respectively. All patients were followed up for 36.8 ± 8.9 months (18-54 months). Only 1 patient with MELF pattern was diagnosed with vaginal recurrence 28 months after the surgery. MELF pattern was associated with adverse histologic findings in endometrial endometrioid carcinomas. However, MELF pattern was statistically not a valuable predictor of lymph node metastasis and it needs more studies to show whether MELF pattern has an impact on the prognosis of patients with endometrial endometrioid carcinoma. MELF pattern may be important for identifying those patients who need comprehensive staging surgery.

Phosphatase and Tensin Homolog Immunohistochemical Expression and Promoter Methylation Status in Endometrioid Endometrial Carcinoma and Its Precursor Lesions.

Endometrioid endometrial carcinoma (EEC) is the most common invasive malignancy of the female genital tract. Despite advances in diagnosis and treatment, the incidence of EEC and mortality related to it have not decreased. Therefore, research is needed to explore the underlying molecular mechanisms of EEC and its precursors to reduce the mortality and societal burden associated with them. Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene most commonly altered in endometrial carcinoma and its precursor lesions. Promoter methylation is a common mechanism for the inactivation of the PTEN tumor suppressor gene. This was a prospective nested case-control study involving women aged 35 to 70 years old whose endometrial biopsy and resected samples were obtained for histological diagnosis. Before enrolling a person in the study, signed informed consent was obtained from each individual. The ethics committee for the institute gave its approval to the study protocol. Immunohistochemistry (IHC) was used to measure PTEN expression was measured, and methylation-specific PCR (MSP) was used to determine PTEN promoter methylation status (Bisulfite conversion). A total of 95 samples were assessed histopathologically, along withPTEN expression and PTEN promoter methylation status. PTEN immunoreactivity was observed in 79% (15/19) of normal proliferative endometrium, and loss of PTEN expression was observed in 73% (27/37) of endometrial hyperplasia with or without atypia and 90% (35/39) of EEC. Methylation analysis showed that the PTEN promoter was completely unmethylated in all normal proliferative endometria and endometrial hyperplasia without atypia. In contrast, the promoter region was methylated in 50% of endometrial hyperplasia with atypia cases and 38.5% of EEC cases. The loss ofPTEN expression was significantly associated with EEC and precancerous lesions of the endometrium compared to normal proliferative endometria. Methylation analysis also revealed that the frequency of methylation is significant in EEC and endometrial hyperplasia with atypia. Integration of PTEN protein expression along with promoter methylation status elucidates the underlying carcinogenic mechanism. This may help with personalized therapy for EECs and triaging cases of potential precancerous lesions.

Single-cell transcriptomic analysis highlights origin and pathological process of human endometrioid endometrial carcinoma

Endometrial cancers are complex ecosystems composed of cells with distinct phenotypes, genotypes, and epigenetic states. Current models do not adequately reflect oncogenic origin and pathological progression in patients. Here we use single-cell RNA sequencing to profile cells from normal endometrium, atypical endometrial hyperplasia, and endometrioid endometrial cancer (EEC), which altogether represent the step-by-step development of endometrial cancer. We find that EEC originates from endometrial epithelial cells but not stromal cells, and unciliated glandular epithelium is the source of EEC. We also identify LCN2 + /SAA1/2 + cells as a featured subpopulation of endometrial tumorigenesis. Finally, the stromal niche and immune environment changes during EEC progression are described. This study elucidates the evolution of cell populations in EEC development at single-cell resolution, which would provide a direction to facilitate EEC research and diagnosis.

Atypical Macropinocytosis Contributes to Malignant Progression: A Review of Recent Evidence in Endometrioid Endometrial Cancer Cells.

Simple SummaryA novel type of macropinocytosis has been identified as a trigger for the malignant progression of endometrial cancer. Transiently reducing epithelial barrier homeostasis leads to macropinocytosis by splitting between adjacent cells in endometrioid endometrial cancer. Macropinocytosis causes morphological changes in well-differentiated to poorly differentiated cancer cells. Inhibition of macropinocytosis promotes a persistent dormant state in the intrinsic KRAS-mutated cancer cell line Sawano. This review focuses on the mechanisms of atypical macropinocytosis and its effects on cellular function, and it describes the physiological processes involved in inducing resting conditions in endometrioid endometrial cancer cells.Macropinocytosis is an essential mechanism for the non-specific uptake of extracellular fluids and solutes. In recent years, additional functions have been identified in macropinocytosis, such as the intracellular introduction pathway of drugs, bacterial and viral infection pathways, and nutritional supplement pathway of cancer cells. However, little is known about the changes in cell function after macropinocytosis. Recently, it has been reported that macropinocytosis is essential for endometrial cancer cells to initiate malignant progression in a dormant state. Macropinocytosis is formed by a temporary split of adjacent bicellular junctions of epithelial sheets, rather than from the apical surface or basal membrane, as a result of the transient reduction of tight junction homeostasis. This novel type of macropinocytosis has been suggested to be associated with the malignant pathology of endometriosis and endometrioid endometrial carcinoma. This review outlines the induction of malignant progression of endometrial cancer cells by macropinocytosis based on a new mechanism and the potential preventive mechanism of its malignant progression.

Evaluation of Lineage/Site-specific Nuclear Immunohistochemical Markers SATB2, Cyclin D1, SALL4, and BCOR in High-grade Endometrial Carcinomas.

Poorly differentiated malignant neoplasms involving the gynecologic tract routinely include a poorly differentiated endometrial carcinoma (EC) in the differential diagnosis. Some nuclear lineage/site-specific immunohistochemical markers are utilized in this diagnostic setting including SATB2, cyclin D1, SALL4, and BCOR, but their specificity and use in small samples are not clear across the spectrum of ECs. Cases of undifferentiated/dedifferentiated endometrial carcinomas (UEC/DDEC), clear cell carcinoma (CCC), uterine serous carcinoma (USC), FIGO grade 3 endometrial endometrioid carcinoma (EEC), and uterine carcinosarcoma (UCS) were identified and diagnoses confirmed. Whole-section immunohistochemical stains for SATB2, cyclin D1, SALL4, BCOR, and PAX8 were performed. A total of 113 cases were utilized: 15 CCC, 26 EEC, 19 UCS, 22 USC, and 31 UEC/DDEC. Cases were distributed across both low (49%) and high (51%) FIGO clinical stages. SATB2 was expressed by UCS (8/19, 42%), EEC (10/26, 38%), UEC/DDEC (11/30, 37%), and USC (6/22, 27%). Cyclin D1 was expressed by EEC (24/26, 92%), USC (17/22, 77%), UEC/DDEC (15/20 EEC component, 75%; 22/30 UEC, 73%), UCS (10/16 carcinoma, 63%; 11/19 sarcoma, 58%), and CCC (8/15, 53%). SALL4 was expressed most frequently by UEC/DDEC (12/30, 40%), but also USC (7/22, 32%), EEC (5/26, 19%), and UCS (4/16 carcinoma, 25%; 3/19 sarcoma, 16%). BCOR was expressed at low levels in 2 USC, 2 UEC/DDEC, and 2 UCS. PAX8 was generally positive but showed lower expression in UEC/DDEC (17/30, 57%) and in the sarcomatous portions of UCS (6/19, 32%). SATB2, cyclin D1, SALL4, and BCOR stain variable numbers of poorly-differentiated EC and must be carefully interpreted within morphologic and clinical context.

Molecular classification and clinicopathological features of endometrial carcinoma

Objective: To investigate the molecular classification and clinicopathological features of endometrial carcinoma(EC). Methods: One hundred cases of EC diagnosed in the Department of Pathology, Tianjin Central Hospital of Gynecology and Obstetrics from November 2020 to November 2021 were selected. Sanger sequencing and immunohistochemical staining were used for molecular classification according to the 5th WHO classification. The clinicopathological characteristics of each molecular subtype was analyzed. Results: The 100 EC patients had a mean age of 53 years (range 26 to 72 years). There were 10 cases of POLE mutation (POLE mut), including two cases (2/10) of "binary-classifier" EC, two cases (2/10) of FIGO Grade 3 endometrioid endometrial carcinoma (G3-EEC), and three cases (3/10) of other high-grade subtypes. There were 38 cases of mismatch repair deficiency (dMMR), including one case (1/38, 2.6%) of "binary-classifier" EC and 36 cases (36/38, 94.7%) were EEC. Twenty-one cases (21/38, 55.3%) showed simultaneous loss of expression of MLH1 and PMS2, and 20 cases (20/21, 95.2%) were positive for MLH1 methylation, indicating that they were sporadic EC. Six patients (6/38, 15.8%) were tested for germline detection of Lynch syndrome (LS) related genes, and one patient was LS-related EC. There were 44 cases of non-specific molecular profile (NSMP), including 34 cases (34/44, 77.3%) of G1-2 EEC and seven cases (7/44, 15.9%) of G3-EEC. There were eight cases of p53 abnormality (p53 abn), including four cases (4/8) of G3-EEC, two cases (2/8) of other high-grade subtypes, and one patient had hereditary breast cancer and ovarian cancer syndrome. Conclusions: Correct interpretation of POLE mutation, MMR and p53 immunohistochemistry is the key of molecular classification. The interpretation must strictly follow standard diagnostic procedures and specifications to ensure the accuracy of molecular classification.