Prognostic impact of histological grade and vascular invasion compared with tumour cell proliferation in endometrial carcinoma of endometrioid type

AIMS: The relative impact of different prognostic factors is important for endometrial carcinoma patients. The aim of our study was to examine the combined value of histological grade [International Federation of Gynaecology and Obstetrics (FIGO)] and vascular invasion in comparison with tumour cell proliferation assessed by mitotic count and Ki67. The recently proposed binary architectural grade was also evaluated, in addition to age, depth of myometrial infiltration and FIGO stage in our population-based series of 237 endometrioid carcinomas. METHODS AND RESULTS: The tumours were studied for several histological features, including FIGO grade, binary grade, vascular invasion, mitotic count, myometrial invasion and expression of Ki67. FIGO grade was significantly associated with all investigated histological features, including Ki67 expression. Vascular invasion was significantly more frequent in FIGO grade 3 tumours, and was associated with a diffusely infiltrative growth pattern, solid growth, necrosis and deep myometrial invasion. All variables showed a highly significant relationship with patient survival in univariate analysis. In multivariate models, FIGO grade, vascular invasion, and proliferation assessed by Ki67 expression all had independent prognostic influence in this population-based study. Comparing tumour cell proliferation (Ki67) with vascular invasion as a marker of metastatic spread, the latter had a stronger survival impact. CONCLUSIONS: Vascular invasion and tumour cell proliferation measured by Ki67 both had independent prognostic influence, and should be considered to identify aggressive tumours of the endometrioid subtype.     

Molecular analysis of isolated tumor glands from endometrial endometrioid adenocarcinomas

We studied the extensive molecular alterations of endometrial endometrioid adenocarcinoma (EEA) using a crypt isolation method. We analyzed copy number variation (CNV) using a single nucleotide polymorphism (SNP) array, genetic mutations (KRAS, BRAF, p53, PIK3CA), DNA methylation and microsatellite instability (MSI) status. In addition, loss of PTEN protein expression was examined. Increased chromosome copy numbers of 1q21.2–44 (22%) and 10q11.21–23.31 (28%) were seen relatively frequently in EEA, and copy‐neutral loss of heterozygosity (LOH) was also observed in 10q22.1–26.3 (22%). The CNV patterns of EEA were classified into four groups through hierarchical cluster analysis. Cluster 1 had many CNVs of 10q, and cluster 2 was characterized by MSI status. In cluster 3, increased CNVs of 1q were often seen. In cluster 4, p53 mutations were detected. KRAS and PIK3CA mutations and reduced PTEN protein expression were common to all groups. On the other hand, CpG island methylator phenotype (CIMP) was rare in all groups. The data indicated an association with chromosomal gain of 1q and 10q or 10q copy‐neutral LOH in some cases. We suggest that EEA consists of four groups that are characterized with molecular alterations.     

Down-regulation of microRNA-124 is correlated with tumor metastasis and poor prognosis in patients with lung cancer

Introduction: MicroRNA-124 (miR-124) has been proven dysregulated in several human malignancies and correlated with tumor progression. However, its expression and clinical significance in non-small cell lung cancer (NSCLC) is still unclear. Thus, the aim of this study was to investigate the clinical significance of miR-124 expression in NSCLC. Methods: Expression levels of miR-124 in 92 pairs of NSCLC and adjacent non-tumor tissues were detected by quantitative real-time PCR (qRT-PCR). In order to determine its prognostic value, overall survival (OS) and disease-free survival (DFS) were evaluated using the Kaplan-Meier method, and multivariate analysis was performed using the Cox proportional hazard analysis. Results: miR-124 expression level was significantly lower in NSCLC tissues compared with adjacent non-tumor tissues (P < 0.05). The 5-year OS of low miR-124 expression group was significantly shorter than that of high miR-124 expression group (P < 0.05). Moreover, the 5-year DFS of low miR-124 expression group was also significantly shorter than that of high miR-124 expression group (P < 0.05). In a multivariate Cox model, we found that miR-124 expression was an independent prognostic factor for both 5-year OS and 5-year DFS in NSCLC (P < 0.05). Conclusions: Our results offer the convincing evidence that miR-124 may play key roles in the progression of lung cancer and that the down-regulated expression of miR-124 may be independently associated with shorter OS and DFS of patients, suggesting that miR-124 might be a potential marker for further risk stratification in the treatment of lung cancer.     

Nuclear features in endometrial cytology: Comparison of endometrial glandular and stromal breakdown and endometrioid adenocarcinoma grade 1

This study was to clarify the nuclear features of “condensed clusters of stromal cells (EGBD‐stromal cells)” and “metaplastic clumps with irregular protrusions (EGBD‐metaplastic cells)” which may be recognized in endometrial glandular and stromal breakdown (EGBD) cases in liquid‐based cytologic (LBC) preparations of endometrial brushings. The material consists of cytologic smears of 20 cases of proliferative endometrium (PE), 20 cases of EGBD, and 20 cases of endometrioid adenocarcinoma grade 1 (G1) for which histopathological diagnosis was obtained by endometrial curettage. Nuclear findings were examined in PE cells, EGBD‐stromal cells, EGBD‐metaplastic cells, and G1 cells, respectively. It was examined about the following items: (1) Nuclear shape; (2) A long/minor axis ratio in cell nuclei; (3) An area of cell nuclei; (4) Overlapping nuclei; (5) The distribution pattern of nuclei within cell clusters. The following observations were made: (1) In PE cells, round‐oval nuclei appeared to predominate, overlapping nuclei were not observed, and a slightly abnormal distribution pattern of nuclei was recorded; (2) In EGBD‐stromal cells, reniform nuclei were characteristically observed, nuclei had small size and a generally elongated appearance, overlapping nuclei were recognized, and a remarkable abnormal distribution pattern of nuclei was found; (3) In EGBD‐metaplastic cells, spindle nuclei were a characteristic feature, nuclei were larger in size and had a bipolar appearance, overlapping nuclei with moderately abnormal distribution pattern of nuclei were identified; (4) In G1 cells round‐oval nuclei predominated, overlapping nuclei with moderately abnormal distribution pattern of nuclei were found. The study demonstrates that the analysis of selected nuclear findings appears to be very useful in the cytopathological assessment of endometrial lesions in LBC samples, especially for the discrimination of EGBD and G1. Diagn. Cytopathol. 2012. © 2012 Wiley Periodicals, Inc.     

Outcomes of the conservative management of the patients with endometrial intraepithelial neoplasia/endometrial cancer: Wait or treat!

Background/aimThe objective of the study was to evaluate the response, relapse, reproductive results and demographic features of the patients with endometrioid adenocancer (EAC) and endometrial intraepithelial neoplasia (EIN) who were treated with conservative treatment. This is the largest study when we consider the single center studies in this field.Materials and methodsIn the current retrospective study, 38 patients (6 EAC, 31 EIN, 1 synchronous tumors of ovary and endometrium) were recruited. They were treated with progesterone products for their fertility desire and comorbidity. Reproductive results, response rates, and recurrence rates were calculated and survival analyses were performed. ResultsMean duration of the medical treatment was 10 months (range 2–60). Among the 32 patients with EIN, 28 (87.5%) had a response, 8 (25%) had a relapse and 4 (12.5%) had persistence. Among the 32 patients who expecting fertility, seven patients got pregnant (21.8%) with a total of five live births. The median follow-up was 40.5 months (range 3–180), and recurrence-free interval was 28.7 months (range 2–180).ConclusionFertility-sparing treatment of EAC and EIN is a feasible approach, and the eligible patients should be given a chance to get pregnant.     

Expression of immunoreactivity of nuclear findings by p53 and cyclin a in endometrial cytology: Comparison with endometrial glandular and stromal breakdown and endometrioid adenocarcinoma grade 1

It is well known that “condensed cluster of stromal cells (CCSC)” and “metaplastic clumps with irregular protrusion (MCIP)” in endometrial glandular and stromal breakdown (EGBD) cases may simulate “clumps of cancer cells (CCC)” in endometrioid adenocarcinoma grade 1 (G1), leading to difficulty in cytological interpretation. The aim of this study was undertaken to clarify the cytological immunoreactivity of nuclear findings about CCSC and MCIP which may be recognized in EGBD cases by using p53 protein and cyclin A in liquid‐based cytologic (LBC) preparations. The material consists of cytologic smears of 20 cases of EGBD and 20 cases of G1 for which histopathological diagnosis was obtained by endometrial curettage at the JA Suzuka General Hospital. The evaluation of immunoreactivity was performed by using the intensity of nuclear staining and the nuclear labeling index (N‐LI). The intensity of nuclear staining was scored as negative (0), weak (1), moderate (2), or strong (3). The N‐LI was scored as less than 10% (0), from 10 to 25% (1), from 26 to 50% (2), or greater than 50% (3). The final score was calculated of the addition of both partial scores. Results are as follows: As for the p53 protein immunoreactivity, CCC (2.4 ± 1.4) was a significantly higher value in comparison with CCSC (0) and MCIP (0.8 ± 0.4), respectively. As for the cyclin A immunoreactivity, CCC (2.8 ± 1.1) was a significantly higher value in comparison with CCSC (0) and MCIP (0.6 ± 0.5), respectively. CCSC and MCIP in EGBD are misunderstood as cellular atypia and structural atypia on occasion; but, as for results of the immunoreactivity scores of p53 protein and cyclin A in our study, it seemed that those biochemical characters proved that the biological activity level was low (or degenerative). The results of the current study demonstrated that the cytological immunoreactivity of nuclear findings by p53 and cyclin A appear to be more useful for the LBC assessment of endometrial lesions, especially for the discrimination of EGBD and G1.Diagn. Cytopathol. 2013;41:303–307. © 2011 Wiley Periodicals, Inc.     

Clinicopathologic study of endometrial dedifferentiated endometrioid adenocarcinoma: a case report

In 2006, dedifferentiated endometrioid adenocarcinoma (undifferentiated carcinoma associated with low-grade endometrioid carcinoma) of the uterus was first proposed. Dedifferentiated endometrioid carcinoma is part of the spectrum of undifferentiated carcinoma of the endometrium which is a highly aggressive tumor even when the undifferentiated component represents only 20% of the entire neoplasm. Therefore, accurate diagnosis and appropriate classification of this neoplasm are important in patient management. Lack of the recognition may lead to misclassification of dedifferentiated endometrioid adenocarcinoma as a pure endometrioid adenocarcinoma which is less aggressive. Only 4 papers have appeared in the literature so far on the topic of dedifferentiated endometrioid carcinoma. We report herein a first case of endometrial dedifferentiated endometrioid carcinoma in a 51-year old woman in Chinese population. We performed immunoperoxidase studies for 12 markers. Among them, cytokeratins, keratin 7, keratin 18, EMA, estrogen receptor (ER), progesterone receptor (PR), and vimentin show significantly differential expression between differentiated and undifferentiated area.     

Expression of long non-coding RNA ZEB1-AS1 in esophageal squamous cell carcinoma and its correlation with tumor progression and patient survival

Background: LncRNA ZEB1-AS1 has been identified as a tumor oncogene in hepatocellular carcinoma. However, the clinical significance in esophageal squamous cell carcinoma (ESCC) is still unknown. The aim of this study was to explore ZEB1-AS1 expression levels and evaluated its clinical significance in ESCC patients. Methods: LNCRNA ZEB1-AS1 expression was determined by quantitative real-time PCR (QRT-PCR) in 87 pairs of ESCC specimens and adjacent non-tumor tissues. Then, the association of ZEB1-AS1 expression with clinicopathological factors or survival of ESCC patients were determined. Results: LNCRNA ZEB1-AS1 was found up-regulated in ESCC tissues compared to adjacent non-tumor tissues. Increased lncRNA ZEB1-AS1 expression was significantly associated with tumor grade, depth of invasion, and lymph node metastasis. Kaplan-Meier analysis revealed that ESCC patients with high ZEB1-AS1 expression had a poorer overall survival and disease-free survival. Furthermore, multivariate analysis suggested that ZEB1-AS1 expression was identified as an independent prognostic factor in patients with ESCC. Conclusion: These results indicated that lncRNA ZEB1-AS1 was associated with tumor progression and could be an independent prognostic factor for ESCC patients.     

Stomatin-like protein 2 expression is associated with clinical survival in patients with cervical cancer

Aims: To investigate the prognostic role of stomatin-like protein 2 (STOML2) in cervical cancer. Methods: The expression of STOML2 in 8 pairs of cervical cancer and adjacent normal cervical tissues were detected by Real-time PCR. Immunohistochemistry was performed to evaluation of STOML2 expression in 94 paraffin-embedded cervical cancer samples. The correlation between STOML2 expression and cervical cancer progression and prognosis was analyzed statistically. Results: STOML2 expression was upregulated in cervical cancer tissues compared with adjacent normal cervical tissues. Of the 94 cervical cancer cases, high STOML2 expression was detected in 54 cases (57.4%). STOML2 expression was significantly related to tumor stage (P = 0.013) and tumor size (P = 0.025). Moreover, patients with high expression of STOML2 had a significant shorter overall survival and recurrent free survival time compared with those with low STOML2 expression in cervical cancer (P = 0.001 and P = 0.017, respectively). Multivariate analysis revealed that STOML2 was an independent prognostic factor (P = 0.022) for the overall survival in cervical cancer. Conclusion: Our study showed STOML2 was correlated to progression in cervical cancer, and implicated it as a potential predictive factor for the prognosis of cervical cancer.     

The AgNORs count in predicting long-term survival in serous ovarian cancer

Introduction

The value of argyrophilic nucleolar organizer regions (AgNORs) to predict survival in patients with ovarian cancer has not been clearly explained yet. The aim of study was to assess the value of analysis of the mean number of AgNORs per nucleus (mAgNOR) and mean percentage of nuclei with five or more AgNORs per nucleus (pAgNOR) in the prediction of disease-free survival (DFS) and overall survival (OS) in patients with serous ovarian cancer.

Material and methods

The study examined 52 patients treated for serous ovarian cancer with a follow-up period of 2-143 months. After silver staining paraffin specimens from primary surgery, mAgNOR and pAgNOR in cancer cells were counted and analyzed. Age, grading, radicality of surgery and FIGO staging were analyzed as covariates.

Results

Mean mAgNOR equaled 4.4 ±0.9 and pAgNOR equaled 42.2 ±20.8%. Both mAgNOR and pAgNOR were the lowest in G1 tumors. The mAgNOR and pAgNOR were lower in stage I than stage IV cancers. The DFS and OS rates were respectively 15.4% and 21.2%. In univariate analysis FIGO staging, grading, and pAgNOR were associated with worse prognosis, while radicality of surgery remained a significant protective factor in terms of DFS. Higher FIGO staging and older age worsened OS. In multivariate analysis FIGO staging remained significantly associated with both DFS (HR 1.98; 95% CI 1.05-3.71) and OS (HR 1.76; 95% CI 1.00-3.10), while age affected OS rates (HR 1.78; 95% CI 1.04-2.95).

Conclusions

mAgNOR and pAgNOR are useful markers of cellular kinetics. Prospective studies in larger populations are needed to confirm these results in terms of AgNORs’ effects on survival.     

术前诊断为子宫内膜不典型增生的子宫内膜癌患者的处理

目的分析和总结术前诊断为子宫内膜不典型增生的子宫内膜癌患者的临床特点及治疗方法。方法 2005年1月至2010年12月北京协和医院妇产科行全子宫切除术后病理诊断为子宫内膜样癌的患者共计404例,其中44例术前子宫内膜活检病理提示子宫内膜不典型增生(AEH),回顾性分析这些患者的临床特点,采用SPSS 13.0统计学软件进行分析。结果 44例术前诊断为AEH的患者中,39例(89%)患者未行子宫内膜癌分期术,子宫切除术后病理均为高分化子宫内膜样癌(100%),14例(32%)年轻患者保留了双侧卵巢,9例(20%)患者给予辅助放疗。中位随诊时间52个月,无复发病例。和绝经后患者相比,绝经前患者术后深肌层浸润(1/22及4/22)及淋巴血管间隙浸润(0/22及3/22)更少,但无统计学差异。比较AEH组和术前诊断为子宫内膜样癌的患者(EC组),AEH组高分化子宫内膜样癌的比例明显高于EC组(P=0.000);辅助化疗率和复发率明显低于EC组(P=0.003和0.019)。结论术前诊刮为AEH的子宫内膜癌患者预后好,年轻患者充分评估后可以考虑保留卵巢,绝经后患者AEH伴发子宫内膜样癌的风险增高,且更容易合并深肌层浸润、淋巴血管间隙受累等高危因素。     

Activated leukocyte cell adhesion molecule (ALCAM) is a marker of recurrence and promotes cell migration,invasion, and metastasis in early‐stage endometrioid endometrial cancer

Endometrial cancer is the most common gynaecological cancer in western countries, being the most common subtype of endometrioid tumours. Most patients are diagnosed at an early stage and present an excellent prognosis. However, a number of those continue to suffer recurrence, without means of identification by risk classification systems. Thus, finding a reliable marker to predict recurrence becomes an important unmet clinical issue. ALCAM is a cell–cell adhesion molecule and member of the immunoglobulin superfamily that has been associated with the genesis of many cancers. Here, we first determined the value of ALCAM as a marker of recurrence in endometrioid endometrial cancer by conducting a retrospective multicentre study of 174 primary tumours. In early‐stage patients (N = 134), recurrence‐free survival was poorer in patients with ALCAM‐positive compared to ALCAM‐negative tumours (HR 4.237; 95% CI 1.01–17.76). This difference was more significant in patients with early‐stage moderately–poorly differentiated tumours (HR 9.259; 95% CI 2.12–53.47). In multivariate analysis, ALCAM positivity was an independent prognostic factor in early‐stage disease (HR 6.027; 95% CI 1.41–25.74). Then we demonstrated in vitro a role for ALCAM in cell migration and invasion by using a loss‐of‐function model in two endometrial cancer cell lines. ALCAM depletion resulted in a reduced primary tumour size and reduced metastatic local spread in an orthotopic murine model. Gene expression analysis of ALCAM‐depleted cell lines pointed to motility, invasiveness, cellular assembly, and organization as the most deregulated functions. Finally, we assessed some of the downstream effector genes that are involved in ALCAM‐mediated cell migration; specifically FLNB, TXNRD1, and LAMC2 were validated at the mRNA and protein level. In conclusion, our results highlight the potential of ALCAM as a recurrent biomarker in early‐stage endometrioid endometrial cancer and point to ALCAM as an important molecule in endometrial cancer dissemination by regulating cell migration, invasion, and metastasis. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Distinction of low-grade endometrioid carcinoma in endometrial samplings from high-grade mimics: a practical pattern-based approach

Low grade endometrioid carcinoma may exhibit a diverse spectrum of morphological variations that mimic high grade cancers. In an endometrial sampling, the distinction between low grade endometrioid carcinoma versus higher grades or other tumor types of carcinoma directly affects clinical decisions regarding the type and extent of surgery and lymph node dissection. This review takes a practical pattern-based approach to this differential diagnosis, highlighting glandular, papillary, solid, spindle-cell, clear-cell rich, mucin-rich, and necrotic patterns of low grade endometrioid carcinoma. Morphological distinctions and immunohistochemical strategies for navigating common diagnostic pitfalls are discussed in alignment with the consensus recommendations on tumor typing from the 2019 International Society of Gynecological Pathologists' Endometrial Cancer Project.     

Prognostic value of pretreatment systemic inflammatory markers in patients with stage I endometrial cancer

Objective: Evaluate the prognostic value of monocyte-lymphocyte ratio (MLR) in patients with stage I endometrial cancer.Method: Data from 225 patients with stage I endometrioid endometrial cancer who underwent surgical resection between January 2010 and December 2020 were reviewed. The receiver operating characteristic (ROC) curves were generated for the neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, and MLR. Optimal cut-off values were determined as the points at which the Youden index (sensitivity + specificity - 1) was maximal. Based on the results of the ROC curve analysis, the patients were grouped into high MLR and low MLR groups. Recurrence rate, and disease-free survival were compared between the two groups. The prognostic factors were investigated using univariate and multivariate Cox proportional hazards model.Results: The optimal cut-off value of MLR was 0.220 (AUC, 0.835; p < 0.001). Significantly more patients in the high MLR group experienced recurrence (20.3% vs. 1.9%, p < 0.0001). In multivariate analysis, grade, depth of myometrial invasion, adjuvant RT, and high MLR were independent prognostic factors for disease-free survival.Conclusion: Elevated MLR was significantly associated poor clinical outcomes in patients with stage I endometrioid endometrial cancer. Our findings suggest that MLR may be clinically reliable and useful as an independent prognostic marker for patients with stage I endometrioid endometrial cancer.     

Prognostic significance of histological grade in low-risk endometrial cancer

Objective: Investigate the risk factors for recurrence in patients with low-risk endometrial cancer.Method: A retrospective review was performed to identify patients who underwent primary surgical treatment for endometrial cancer from December 2009 to December 2020. Patients who met the following criteria were included in the study: (a) International Federation of Gynecology and Obstetrics stage IA, (b) endometrioid-type histology, (c) histological grade 1 or 2.Univariate and multivariate analyses using Cox proportional hazards model to evaluate effects of prognostic factors. Disease-free survival and overall survival were calculated using the Kaplan-Meier method.Results: A total of 171 patients with low-risk endometrial cancer were included in the study. Recurrence was detected in 9 patients. Histological grade was found to be independent risk factors for recurrence in women with low-risk endometrial cancer (OR 8.255, 95% confidence interval (CI) 1.585 - 42.981; p = 0.012).Conclusion: The results of this study suggest that grade 2 disease should be considered a significant prognostic factor for the recurrence of low-risk endometrial cancer.     

Prediction of lymphovascular space invasion in patients with endometrial cancer

Objective: Predict the presence of lymphovascular space invasion (LVSI), using uterine factors such as tumor diameter (TD), grade, and depth of myometrial invasion (MMI). Develop a predictive model that could serve as a marker of LVSI in women with endometrial cancer (EC).Methods: Data from 888 patients with endometrioid EC who were treated between January 2009 and December 2018 were reviewed. The patients'' data were retrieved from six institutions. We assessed the differences in the clinicopathological characteristics between patients with and without LVSI. We performed logistic regression analysis to determine which clinicopathological characteristics were the risk factors for positive LVSI status and to estimate the odds ratio (OR) for each covariate. Using the risk factors and OR identified through this process, we created a model that could predict LVSI and analyzed it further using receiver operating characteristic curve analysis.Results: In multivariate logistic regression analysis, tumor size (P = 0.027), percentage of MMI (P < 0.001), and presence of cervical stromal invasion (P = 0.002) were identified as the risk factors for LVSI. Based on the results of multivariate logistic regression analysis, we developed a simplified LVSI prediction model for clinical use. We defined the “LVSI index” as “TD×%MMI×tumor grade×cervical stromal involvement.” The area under curve was 0.839 (95% CI= 0.809-0.869; sensitivity, 74.1%; specificity, 80.5%; negative predictive value, 47.3%; positive predictive value, 8.6%; P < 0.001), and the optimal cut-off value was 200.Conclusion: Using the modified risk index of LVSI, it is possible to predict the presence of LVSI in women with endometrioid endometrial cancer. Our prediction model may be an appropriate tool for integration into the clinical decision-making process when assessed either preoperatively or intraoperatively.     

DNA methyltransferase 3a rs1550117 genetic polymorphism predicts poor survival in gastric cancer patients

DNA methyltransferase 3a (DNMT3a) have been suggested to play a crucial role in human cancer prognosis. Single nucleotide polymorphisms (SNPs) in DNMT3a genes may have an impact on the prognosis of cancers. This study aimed to investigate the association between SNPs of DNMT3a gene and prognosis of gastric cancer (GC). Two sites of DNMT3a SNPs, rs1550117 and rs13420827 were selected and genotyped using TaqMan assay in 447 GC patients who received gastrectomy. Effects of genotypes on clinical outcomes of GC were calculated by Kaplan-Meier survival analysis and Cox regression model. We found that the AG or AA genotype of rs1550117 was associated with significantly poorer survival and increased death risk of GC compared with GG genotype (dominant model: HR=1.35, 95% CI=1.01-1.80, P=0.043). Further multivariate Cox regression analysis revealed that in addition to the known factors including male, larger tumor sizes and high clinical stage, rs1550117 variant was an independently predictive factor for survival in GC patients. No significant association was found between rs13420827 genetic variants and GC prognosis. Our findings first demonstrated that DNMT3a rs1550117 polymorphism may be a potential biomarker in predicting overall survival of GC patients.