Endometrial Cancer Metastasis Research Articles

Fibulin-4 is associated with prognosis of endometrial cancer patients and inhibits cancer cell invasion and metastasis via Wnt/β-catenin signaling pathway.

Fibulin-4, an extracellular glycoprotein, which plays significant roles in elastic fiber assembly, is correlated to the progression of some cancers. However, the role of fibulin-4 in endometrial cancer cell invasion and metastasis remains unexplored. In our study, fibulin-4 expression was assessed by immunohistochemistry (IHC) and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in normal endometrial tissues and endometrial carcinoma tissues. Using single cell cloning, strongly, and weakly, invasive subclones were derived from KLE and Ishikawa endometrial carcinoma cell lines. RT-qPCR, western blotting, and immunocytochemistry (ICC) were used to assess mRNA and protein expressions of fibulin-4 in primary cultured endometrial cells, 4 types of endometrial cancer cell lines, and the different invasive subclones. Using lentivirus transfection, fibulin-4 shRNA and pLVX-fibulin-4 were constructed and used to infect the strongly and weakly invasive subclones. The effects of fibulin-4 on the biological characteristics of endometrial carcinoma cells were detected by cell functional assays in vitro and in vivo. Using Wnt signaling pathway inhibitor XAV-939 and activator LiCl, we detected the role of fibulin-4 in the Wnt/β-catenin pathway and the relationship with epithelial to mesenchymal transition (EMT). Fibulin-4 was decreased in endometrial carcinoma tissues, and loss of fibulin-4 expression was significantly related with poor differentiation, lymph node metastasis, and poor prognosis of endometrial carcinoma. Fibulin-4 significantly inhibited endometrial carcinoma cell proliferation, invasion, metastasis, and EMT through the Wnt/β-catenin pathway. Fibulin-4 has the ability to suppress endometrial cancer progression. These results can contribute to the development of a new potential therapeutic target for patients with endometrial carcinoma.

A preoperative and intraoperative scoring system to predict nodal metastasis in endometrial cancer.

To develop a scoring system that guides surgical decision-making regarding the need to perform lymphadenectomy. A retrospective study was performed of patients who underwent complete surgical staging of endometrial cancer between 2003 and 2014 at three centers in Brazil. Preoperative and intraoperative risk factors were used to develop a scoring system to predict lymph node metastasis. Among 329 patients included, 71 (21.6%) had positive lymph nodes and 259 (78.4%) had negative lymph nodes. The characteristics associated with nodal metastasis in univariate analysis included the level of cancer antigen 125 (P<0.001), preoperative histological grade (P<0.001), endometrial thickness (P=0.012), and pathologic features including tumor size (P<0.001), tumor extension (P<0.001), and lower uterine segment involvement (P<0.001). On multivariate logistic regression analysis, tumor grade, tumor extension, and lower uterine segment involvement remained significantly associated. The resulting scoring system showed good accuracy as demonstrated by an area under the receiver operating characteristic curve of 0.858 (95% confidence interval 0.804-0.913). A highly accurate scoring system for the prediction of lymph node metastasis was developed on the basis of three preoperative and intraoperative risk factors. After validation, this model could greatly aid clinicians in the surgical management of endometrial cancer.

Determinants of pelvic and para-aortic lymph node metastasis in endometrial cancer and its role in tailoring lymphadenectomy

Determinants of pelvic and para-aortic lymph node metastasis in endometrial cancer and its role in tailoring lymphadenectomy

Endometrium Kanserinde Prezentasyon Bulgusu Olarak Asetabulum Metastazı

Acetabulum is uncommon extraordinary place for endometrial cancer metastasis. Here we report a case of primary bone metastasis as initial presentation of the endometrial cancer. A 67 years old nulliparous Turkish woman admitted to the hospital with right hip pain. Magnetic resonance imaging was realized and a mass in size of 40x66 mm was reported in the posterior of the right acetabulum. Biopsy of the mass was taken and the result was recorded as metastatic adenocarcinoma. PET CT revealed that a mass of approximately 78x63 mm on the right acetabulum and a heterogeneous increase of F-18 FDG uptake (SUVmax: 11.8) was noticed. Further, irregular enlarged endometrial cavity and increased F-18 FDG involvement (SUVmax:13,4) were observed. Endometrial biopsy was applied and the result was reported as endometrial adenocarcinoma FIGO grade 2. In conclusion, endometrial biopsy should be included in the women patient's screening when investigated for metastatic bone adenocarcinoma.

Preoperative assessment of lymph node metastasis in endometrial cancer: A Korean Gynecologic Oncology Group study

Previously proposed criteria for preoperatively identifying endometrial cancer patients at low risk for lymph node metastasis remain to be verified. For this purpose, a prospective, multicenter observational study was performed. Eligible patients with histologically confirmed endometrial cancer underwent magnetic resonance imaging (MRI) and serum cancer antigen 125 (CA 125) testing before surgery. The following criteria were used to identify low-risk patients: 1) endometrioid-type cancer, 2) no evidence of deep myometrial invasion on MRI, 3) no enlarged lymph nodes on MRI, 4) no suspicious metastasis out of the uterine corpus, and 5) serum CA 125 levels less than 35 U/mL. Systematic pelvic and/or para-aortic lymphadenectomy was performed for all patients. The primary endpoint was estimation of the negative predictive value (NPV). From January 2012 to December 2014, 529 patients from 20 hospitals in 3 Asian countries were consecutively enrolled. According to our criteria, 272 patients (51.4%) were categorized into the low-risk group. Fifty-three of the 529 patients (10.0%) had lymph node metastases; these patients included 8 (2.9%) falsely categorized as low-risk. The sensitivity and specificity of the criteria were 84.9% and 55.5%, respectively. The NPV of 97.1% was higher than the predefined target endpoint of 96%. The low-risk criteria based on preoperative tests were confirmed to be reliable and accurate for identifying patients at low risk for lymph node metastasis. These criteria may facilitate patient counseling and surgical decision making. Cancer 2017;123:263-272. © 2016 American Cancer Society.

Predictive value of serum HE4 and CA125 concentrations for lymphatic metastasis of endometrial cancer.

To evaluate the predictive value of serum HE4 and CA125 concentrations in the preoperative prediction of risk of lymph node metastasis in endometrial cancer. A retrospective study was undertaken of data for patients with endometrial carcinoma treated surgically at a university hospital in China between August 2011 and December 2015. The preoperative serum levels of HE4 and CA125 were measured and analyzed by clinicopathologic characteristics. Overall, 258 patients were included. The HE4 and CA125 concentrations were significantly elevated in patients with large lesions (≥2cm), deep myometrial invasion (≥50%), an advanced disease stage, or lymph node metastasis (P<0.05 for all). HE4 concentrations also rose with age and histologic grade (P<0.01 for both). For lymph node metastasis, HE4 had higher sensitivity and negative predictive value than did CA125. The diagnostic performance of HE4 and CA125 in combination was superior to that of either marker alone. The combined evaluation of serum HE4 and CA125 could provide gynecologic oncologists with improved information to guide the decision of whether to perform lymphadenectomy.

Overexpression of microRNA-205 predicts lymph node metastasis and indicates an unfavorable prognosis in endometrial cancer

As an integral component of the surgical staging system, lymphadenectomy for patients with endometrial cancer (EC) remains controversial, particularly in clinical stage I disease that includes not only low-risk, but also high-risk subgroups. In order to maximize the therapeutic effect of lymph node excision for high-risk patients who can potentially obtain survival benefits from it while minimizing its reverse effects in low-risk patients, pre-operative risk stratification of lymph node metastasis is necessary. The upregulation of microRNA-205 (miR-205) in carcinoma of the endometrium has been consistently reported recently and has been found to correlate with poor survival. The current study aimed to investigate whether the overexpression of miR-205 in curettage samples of EC could identify patients who are at a high risk for lymph node metastasis prior to surgery and validate the role of miR-205 as a prognostic marker in EC. Relative quantification detection of miR-205 in curettage and hysterectomy specimens of patients with EC was performed. Prediction of lymph node metastasis based on miR-205 expression, as well as tumor type and grade in curettage samples, was performed for all EC patients and patients with clinical stage I disease. Moreover, survival analysis was conducted. It was observed that miR-205 was significantly and consistently elevated in the curettage and hysterectomy samples of EC relative to normal controls. Furthermore, the overexpression of miR-205 could predict lymph node metastasis with a high accuracy and was revealed again to be associated with a poor prognosis in EC. Prospective and multicentric studies are required to further clarify the value of miR-205 as a promising predictor to stratify risk for lymph node metastasis in EC.

AXL modulates extracellular matrix protein expression and is essential for invasion and metastasis in endometrial cancer.

The receptor tyrosine kinase AXL promotes migration, invasion, and metastasis. Here, we evaluated the role of AXL in endometrial cancer. High immunohistochemical expression of AXL was found in 76% (63/83) of advanced-stage, and 77% (82/107) of high-grade specimens and correlated with worse survival in uterine serous cancer patients. In vitro, genetic silencing of AXL inhibited migration and invasion but had no effect on proliferation of ARK1 endometrial cancer cells. AXL-deficient cells showed significantly decreased expression of phospho-AKT as well as uPA, MMP-1, MMP-2, MMP-3, and MMP-9. In a xenograft model of human uterine serous carcinoma with AXL-deficient ARK1 cells, there was significantly less tumor burden than xenografts with control ARK1 cells. Together, these findings underscore the therapeutic potentials of AXL as a candidate target for treatment of metastatic endometrial cancer.

One-step nucleic acid amplification (OSNA) for the detection of sentinel lymph node metastasis in endometrial cancer

ObjectiveTo evaluate the efficacy of one-step nucleic acid amplification (OSNA) for the diagnosis of sentinel lymph node (SLN) metastasis compared with histopathological examination in patients with endometrial carcinoma. MethodsA total of 94 SLNs from 34 patients with endometrial carcinoma were enrolled. The central 1-mm portion of each node was subjected to semi-serial sectioning, sliced at 200-μm intervals and examined by hematoxylin and eosin and cytokeratin 19 (CK19) immunohistochemical staining, and the remaining tissue was analysed by OSNA using CK19 mRNA. The accuracy of the OSNA assay was evaluated based on histopathological diagnosis. ResultsHistologically, 89 SLNs were determined to be metastasis negative, and the remaining five SLNs were metastasis positive. Using the breast cancer cutoff value for detecting lymph node metastasis (OSNA criteria for breast cancer, >250copies/μl) the sensitivity of the OSNA assay was 100%; specificity was 87.6%; diagnostic accuracy was 88.3%. Discordant results were recorded for 11 of 94 SLNs. In all 11 cases, a positive result was given by the OSNA assay but not by histopathological examination. In two SLNs from the same patient, histopathological examination revealed the presence of benign epithelial inclusions that were CK19 positive; both SLNs yielded a positive result in the OSNA assay (true–false positive). All remaining nine histologically-negative/OSNA-positive SLNs were classified as micrometastasis (+) by the OSNA assay. ConclusionThe OSNA assay shows high sensitivity and specificity, which suggests its utility as a novel tool for the molecular detection of SLN metastasis in patients with endometrial carcinoma.

Silencing of UCA1, a poor prognostic factor, inhibited the migration of endometrial cancer cell.

Endometrial cancer (EC) is a common female malignancy. Most patients were diagnosed at an early stage with a favorable prognosis. But more than 30% patients were high risk at III/IV stage with invading deep into the myometrium and progressively lead to local or extra pelvic metastasis. Urothelial cancer-associated 1 (UCA1) had been reported as the oncogenic long non-coding RNA in many tumors, but the role of UCA1 in EC is still unclear. QRT-PCR was used to analysis the level of UCA1 in the proliferative endometrium, primary EC tissue and lymph node metastasis tissue of EC. According to the QRT-PCR results of primary EC tissue, survival curves were made using the Kaplan-Meier method, and the log rank test was used to analyze the differences of clinicopathological characteristics and survival between the low expression and high expression group of UCA1 in EC patients. Moreover we knocked down the expression of UCA1 in EC cell lines HTB-111 and Ishikawa, and detected the migration and invasion ability of them with wound healing assay and transwell assay. The expression level of UCA1 using QRT-PCR method in lymph node metastasis tissue was the highest than that in the proliferative endometrium and primary EC tissues (1.15 ± 0.23, 3.23 ± 1.06 vs. 6.42 ± 1.46, P < 0.0001). For the primary EC tissue, the median fold change of UCA1 was used as a cutoff value. High UCA1 expression was observed to be closely correlated with lymph node metastasis (P = 0.008), distant metastasis (P = 0.003), grade (P = 0.009), advanced TNM stage (P = 0.031) and vessel invasive (P = 0.032). The 5-year overall survival rate in the high expression group was 41.7%, compared with 72.7% in the low expression group (P = 0.023). After silencing the UCA1, the migration and invasion ability of EC cell lines reduced significantly. Our findings provide the convincing evidence that the UCA1 plays an important role in the metastasis of EC and may serve as a novel molecular marker to predict the aggressive tumor progression and unfavorable prognosis of EC patients.

MiR-10b Inhibits Apoptosis and Promotes Proliferation and Invasion of Endometrial Cancer Cells via Targeting HOXB3.

MicroRNAs are small RNA that are tightly interrelated with the initiation, development, and metastasis of cancers. Studies have shown that miR-10b is increased in various cancers. However, the underlying mechanisms of miR-10b in the occurrence and metastasis of endometrial cancer are poorly understood. To investigate its roles and correlations with Homeobox box 3 (HOXB3) in endometrial cancer, cancer tissues and adjacent normal endometrium tissues from 20 patients with endometrial cancer were studied. miR-10b expression was significantly up-regulated (p < 0.01) in endometrial cancer tissue, whereas HOXB3 was lowly expressed. The silence of miR-10b resulted in significantly enhanced cell apoptosis, and remarkably reduced cell proliferation, migration, and invasion (p < 0.05). Moreover, the protein levels of HOXB3 were increased in KLE cells with silenced miR-10b, and dual-luciferase reporter assay suggested that miR-10b could directly target HOXB3. Furthermore, overexpression of HOXB3 promoted cell apoptosis but inhibited cell proliferation, migration, and invasion (p < 0.01). To conclude, miR-10b might control cell apoptosis, proliferation, migration, and invasion in endometrial cancer via regulation of HOXB3 expression.

Cannonball lung metastases as a presenting feature of ectopic hCG expression

Cannonball metastases refer to well-defined spherical nodules scattered over both lungs, being a classical presentation of hematogenous tumor spreading. Striking progression of lung metastases without established primary malignancy can raise a diagnostic challenge. We herein report three cases with cannonball metastases at initial presentation. Two patients ended up having a choriocarcinoma but no awareness of the presence of primary tumors, and the third had abrupt lung metastases of endometrial cancer while she was being asymptomatic. Relentless progression was illustrated by clinical and radiographic changes. Ectopic expression of human chorionic gonadotropin (hCG) would seemingly go some way responsible for fulminant cancer spreading associated with poor prognosis in our patients. The goal of this presentation is to raise awareness of ectopic hCG expression in patients presenting with similar astonishing scenarios.

Liver recurrence in endometrial cancer: a multi-institutional analysis of factors predictive of postrecurrence survival.

Predictive factors for survival following liver metastasis in endometrial cancer (EC) have not been studied to date. It is expected that patients who initially presented with liver metastasis or developed liver metastasis as the subsequent metastatic site of progressive disease are likely to have poor outcomes. However, patients developing liver metastasis as the first site of recurrence may have a chance of benefiting from the salvage therapies. Therefore, we aimed to determine factors influencing postrecurrence survival in EC patients who developed liver metastasis as the first site of recurrence. Patients with EC who underwent primary surgery at three centers between 1993 and 2013 were reviewed. Liver recurrence was defined as documentation of parenchymal liver metastasis either by radiologically or biopsy, after a disease-free interval of ≥3months. Patients with liver metastasis at presentation, or liver metastasis as the subsequent metastatic site of progressive disease were excluded. Forty-six patients were identified. Median time to liver recurrence was 12months, with 91.3% of recurrences detected within 3years. Most patients (73.9%) had liver recurrence concomitant with extra-hepatic disease. Median survival after the diagnosis of liver recurrence was 9months. While in univariate analysis, time to liver recurrence (p<0.001) and presence of concomitant extra-hepatic metastasis (p=0.048) were potential predictors of survival, multivariate analysis revealed that time to liver recurrence (p<0.001) was the only independent predictor. This criterion may be used as a marker for stratifying patients into different prognostic risk groups and for selection of patients for salvage therapies.

Promotion of epithelial-mesenchymal transition by Frizzled2 is involved in the metastasis of endometrial cancer

The Wnt signaling pathway is essential for embryonic development, and genetic alteration in this network is closely correlated with tumorigenesis and progression. Previous research has shown that Wnt receptor Frizzled2(Fzd2) is elevated in many metastatic cancer cell lines and high grade tumors. Yet, little is known about the Fzd2 expression and activity in human endometrial cancer(EC). In this study, we present evidence of a direct role of Fzd2 in human EC. We found that Fzd2 expression was higher in EC than that in adjacent normal tissues, and was correlated with epithelial‑mesenchymal transition markers. Next, it was determined that the stable overexpression of Fzd2 in HEC-1B and Ishikawa cells promoted cell migration and induced an EMT phenotype. Conversely, RNA interference-mediated depletion of Fzd2 inhibited EC cell migration. Additionally, mechanistic investigation revealed that elevated Fzd2 expression activated canonical Wnt signaling and was blocked by canonical Wnt signaling inhibitor XAV939. However, Fzd2 did not influence the proliferation of EC cells. Thus, Fzd2 may be a potential marker for EC metastasis and a target for future therapies for this disease.

A preoperative risk-scoring system to predict lymph node metastasis in endometrial cancer and stratify patients for lymphadenectomy

ObjectiveThis study aimed to validate the preoperative scoring system adopted in the Kanagawa Cancer Center (KCC) to stratify endometrial cancer patients for lymphadenectomy according to the risk of developing lymph node metastasis (LNM). MethodsThe records of 432 and 221 uterine cancer patients treated in the KCC and Yokohama City University (YCU), respectively, were retrospectively analyzed. The KCC classified patients for LNM risk based on tumor volume, myometrial invasion, histological grade, and serum CA125 levels, while YCU used only myometrial invasion. Lymphadenectomy was omitted for 156 patients with 0 LNM risk, while pelvic lymphadenectomy (PLX) or PLX with para-aortic lymphadenectomy (PLAX) were performed for those with low and high LNM risk, respectively. The predicted and actual LNM rates were compared between the KCC and YCU patients, and cancer recurrence and overall survival were analyzed. ResultsThere was no difference in survival between patients with LNM score 0 who were or were not treated with lymphadenectomy. None (0%) developed LNM and only 1 (0.6%) had recurrence. Patients who underwent PLX but not PLAX (low LNM score) had a low tumor recurrence rate in the para-aortic nodes (1.3%). The KCC scoring system was significantly more accurate than the YCU system in predicting LNM in the high-risk group (P<0.05) and demonstrated that PLAX was unnecessary in almost 50% of the YCU cases. ConclusionThe KCC preoperative scoring system is useful to predict LNM risk, and thereby prevent unnecessary lymphadenectomy or to determine its extent in endometrial cancer patients.

Prognostic factors for adnexal metastasis in endometrial cancer and its implication for ovarian preservation

Prognostic factors for adnexal metastasis in endometrial cancer and its implication for ovarian preservation

Genetic inactivation of the receptor tyrosine kinase AXL inhibits invasion and metastasis in metastatic endometrial cancer

Genetic inactivation of the receptor tyrosine kinase AXL inhibits invasion and metastasis in metastatic endometrial cancer

The value of FDG-PET/CT in node-negative endometrial cancer on MRI

Objectives: To evaluate the diagnostic performance of preoperative fluorodeoxyglucose positron emission tomography–computed tomography (FDG-PET/CT) in predicting lymph node status in node-negative endometrial cancer on preoperative magnetic resonance imaging (MRI). Methods: Patients with endometrial cancer who underwent both preoperative MRI and FDG-PET/CT and then underwent hysterectomy and lymphadenectomy were included. MRI and FDG-PET/CT images were independently reviewed by 2 radiologists and 2 nuclear medicine physicians blinded to the clinical and pathologic information and the results of FDG-PET/CT or MRI. Lymph nodes smaller than 1 cm in short axis diameter were defined as negative lymph nodes on MRI. Lymph nodes were divided into 8 lymph node stations in each patient. The diagnostic performance of PET-CT in predicting lymph node metastasis was calculated in a patient-by-patient analysis and lymph node station-by-station analysis. Results: A total of 362 patients did not have lymph node metastasis on preoperative MRI. All patients underwent pelvic lymph node dissection, and 118 patients underwent para-aortic lymph node dissection. A total of 10,238 lymph nodes were retrieved from 2,099 lymph node stations. Twenty-seven patients had lymph node metastasis on pathologic examination. PET-CT diagnosed only 5 patients (18.5%) with lymph node metastasis. The sensitivity of FDG-PET/CT was 18.5% in patient-by-patient analysis. Lymph node metastasis was found in 49 lymph node stations on pathologic examination. PET-CT diagnosed only 8 lymph node stations (16.3%) with lymph node metastasis. The sensitivity of FDG-PET/CT was 16.3% in lymph node station-by-station analysis. The median diameter of false-negative metastatic lymph nodes was 6 mm (range, 1–22 mm) in long axis and 3 mm (range, 1–11 mm) in short axis. Conclusions: This study indicates the low value of preoperative FDG-PET/CT in predicting lymph node metastasis in node-negative endometrial cancer on preoperative MRI.

Vaginal implantation metastasis of endometrial carcinoma: A case report.

Endometrial cancer is the most common malignancy of the female reproductive system. The three common spread patterns of endometrial cancer are local invasion, lymphatic spread and hematogenous spread. Vaginal metastasis occurs by submucosal lymphatic or vascular metastases in ~10% of patients with clinical stage I disease. Vaginal implantation metastasis of endometrial cancer is extremely rare. Here we present a case of endometrial carcinoma (International Federation of Gynecology and Obstetrics stage IA) spread to the vagina by implantation metastasis as opposed to any of the methods mentioned above. This conclusion was confirmed mainly from pathological examination. This case highlights the occurrence of vaginal implantation metastasis of endometrial carcinoma. Certain changes may be applied during surgery to prevent implantation metastasis in patients with endometrial cancer.

Evaluation of models to predict lymph node metastasis in endometrial cancer: A multicentre study

BackgroundSeveral models (preoperative and postoperative) have been developed to predict lymph node metastasis (LNM) in patients with endometrial cancer. The purpose of our investigation was to compare available models in a multicentre study. MethodsIn a cohort of 519 patients with endometrial cancer who had undergone primary hysterectomy and at least a pelvic lymphadenectomy, we compared the areas under the receiver-operating characteristic curves (AUCs), calibrations, rates of false negatives (FN), and the number of patients at low-risk for LNM using ten different models (three preoperative and seven postoperative). ResultsIn all, 17.5% of patients among the study population (91 in 519) had LNM. Only one of the three preoperative models and three of the seven postoperative models had an AUC >0.75. Six models were well calibrated. Eight models yielded an FN rate of <5%. Six models could assign more than a third of patients to the low-risk group. One postoperative (a French nomogram) and one preoperative (the Korean Gynecologic Oncology Group [KGOG]) model had an AUC >0.75, to yield an FN rate of <5%, and could assign more than a third of patients to the low-risk group. ConclusionsThis study supports the use of the KGOG model to decide upon lymphadenectomy preoperatively in patients with endometrial cancer. For patients who did not have lymphadenectomy, a French nomogram could be applied using pathological characteristics to decide on a secondary lymphadenectomy.