Endometriosis-associated Ovarian Cancer Research Articles

Infiltrating T lymphocytes and programmed cell death protein-1/programmed death-ligand 1 expression in endometriosis-associated ovarian cancer

To characterize T lymphocyte infiltration and programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) expression in early-stage endometriosis-associated ovarian cancer (EAOC), ovarian endometriosis (OE), atypical endometriosis (AE), and deep endometriosis (DE). Case-control, retrospective study. Research University Hospital. A total of 362 patients with a histologic diagnosis of EAOC, OE, AE, or DE were identified between 2000 and 2019 from Fondazione Policlinico Universitario Agostino Gemelli IRCCS and Gemelli Molise SpA tissue data banks. A 1:1 propensity score-matched method yielded matched pairs of 55 subjects with EAOC, 55 patients with OE, 12 patients with AE, and 42 patients with DE, resulting in no differences in family history of cancer, parity, and use of oral contraceptives. Immunohistochemistry assays using the following primary antibodies: CD3+; CD4+; CD8+; PD-1; and PD-L1. To characterize T lymphocyte infiltration and PD-1/PD-L1 expression in 4 different endometriosis-related diseases. Endometriosis-associated ovarian cancer cases displayed significantly higher levels of PD-1/PD-L1 expression compared with all other endometriosis-related diseases (vs. OE vs. AE vs. DE). Moreover, a significantly lower count of infiltrating T lymphocytes was observed in EAOC cases compared with OE ones. Finally, one-third of OE cases showed a cancer-like PD-1/PD-L1 expression profile. Endometriosis-associated ovarian cancer is characterized by higher levels of PD-1/PD-L1 expression compared with benign endometriosis-related diseases. This profile was found in one-third of clinically benign cases, suggesting that it develops early in the carcinogenesis process.

The High Expression of RRM2 Can Predict the Malignant Transformation of Endometriosis.

A large number of epidemiological studies have revealed that women with endometriosis (EMS) have a higher risk of developing endometriosis-associated ovarian cancer (EAOC). At present, there are few studies on predicting the malignant transformation of ovarian endometriosis (OE). The purpose of this study is to identify and verify the molecules that may be able to predict the malignant transformation of OE. The gene expression profiles of ovarian cancer and OE were downloaded from Gene Expression Omnibus (GEO), and a common hub gene ribonucleotide reductase M2 (RRM2) was identified. A total of 44 patients with EAOC and 44 with OE were enrolled in this study. Immunohistochemistry (IHC) and quantitative reverse transcription polymerase chain reaction (RT-qPCR) were used to detect the expression of RRM2, while the relationship between RRM2 and Ki-67 was analyzed by IHC co-localization. Bioinformatics analysis showed that the expression of RRM2 was low in EMS and high in ovarian cancer. RRM2 was obviously positively expressed in eutopic endometrium (EU), ectopic endometrium (EC), and cancer tissues of EAOC patients. The IHC signal and mRNA levels of RRM2 were higher in the EC of EAOC patients compared with OE patients (P<0.01). In addition, there was a correlation between the expression of RRM2 and Ki-67 in EC of EAOC patients (P<0.01). The upregulated expression of RRM2 in the EC of OE patients may indicate malignant transformation. High expression of RRM2 promotes abnormal proliferation of histiocytes. RRM2 can be used as a potential marker of malignant transformation of OE.

O-066 The naughty genes and 3D structure of the endometrium

Abstract The naughty genes and 3D structure of the endometrium Takayuki Enomoto, Manako Ymaguchi, Kazuaki Suda, Kosuke Yoshihara Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. The human endometrium is a highly regenerative tissue and involved in menstruation and implantation of the fertilized egg, giving it a central role in women’s reproductive health. However, the regenerative nature of the endometrial glands can lead to the development and progression of “endometrium-related diseases” such as adenomyosis, endometriosis, endometriosis-associated ovarian cancer, endometrial hyperplasia, and endometrial cancer. To clarify the pathogenesis of endometrium-related diseases and develop effective preventative measures and therapeutic strategies, comprehensive understanding of molecular biological linkage between endometrium and endometrium-related diseases was crucially important. To this end, we focused on genomic alterations of endometrial epithelium which is considered the origin of endometriosis, and sequenced 107 ovarian endometriotic and 82 normal uterine endometrial epithelium samples isolated by laser-microdissection. Intriguingly, several genes recurrently mutated in endometriosis-associated ovarian cancers were frequently mutated in both endometriotic epithelium and normal uterine endometrial glands. In particular, PIK3CA mutation was detected in 41% of endometrial epithelium subjects but none of them had shared PIK3CA mutations across multiple regions collected from the same individuals. Mutation allele frequencies of somatic mutations in uterine endometrial epithelium samples were also significantly lower than those in ovarian endometriotic epithelium samples, suggesting the heterogeneous genomic compositions in uterine endometrium. To interpret this genomic heterogeneity in uterine endometrium, we focused on endometrial gland, the minimum functional unit of uterine endometrium, and conducted 109 single endometrial glands sequencing. As a result, we unveiled that each gland carried distinct somatic mutations in cancer-associated genes, such as PIK3CA, KRAS, and PTEN, with high mutant allele frequencies, suggesting the monoclonality of each gland. The presence of cancer-associated gene mutations in histologically normal endometrial glands provides important clues regarding the pathogenesis of endometrium-related diseases. However, our previous study could not determine the spread of endometrial gland harboring cancer-associated gene mutation because there is a limitation to two-dimensional assessment of the whole shapes of endometrial gland due to its complicatedly winding morphology. Therefore, we tackled with three-dimensional (3D) assessment of human endometrium. To construct a large picture of endometrial gland structure, we performed tissue-clearing-based 3D imaging of full-thickness human uterine endometrial tissue with the use of light-sheet fluorescence microscopy. Our 3D immunohistochemistry discovered some new and unique 3D morphologies of endometrial glands, including plexus network of glands or occluded glands. Notably, computational analysis of 3D layer clarified that the plexus structure of the glands was mainly located in the stratum basalis and expanded along muscular layer horizontally, similar to the so-called “rhizome of grass”. Although previous studies have shown the 3D structure of murine endometrial glands, the bottom of these glands forms a crypt but not a rhizome. This can potentially be explained by the existence of menstruation, which is the crucial difference between the human and murine endometrium. The rhizome structure of endometrial gland in the human endometrium will have a functional advantage over the crypt in terms of the conservation of progenitor/stem cells and regeneration. In addition, some endometrial glands shared the plexus and rose toward the luminal epithelium, suggesting that these glands were the same origin. The rhizome of the endometrium may be a crucial element for understanding the expansion of endometrial glands harboring cancer-associated gene mutations. Integrated analysis of the naughty gene alterations and the 3D structure in human endometrium will lead to a better understanding of the human endometrium in various fields, including histology, pathology, pathophysiology, reproduction, and oncology.

The rhesus macaque: a unique and compelling model for human endometriosis-associated ovarian carcinomas

Objectives: Clear cell ovarian carcinoma and endometrioid ovarian carcinoma (EnOC) are considered endometriosis-associated ovarian cancers (EAOCs). Given no higher order animal model currently exists for these cancers, we propose a novel animal model, the rhesus macaque (Macaca mulatta), for better understanding malignant transformation from endometriosis to EAOCs. Methods: The Wisconsin National Primate Research Center (WNPRC) maintains a multigenerational colony of Indian-derived rhesus macaques with well-documented incidence of spontaneous endometriosis. WNPRC researchers developed a model in which estrogen receptor-a was knocked down in the hypothalamus (hypoER-a) of adult rhesus females. Standard hemotoxylin and eosin (HE) and progesterone receptor (PR). Results: Twelve animals were evaluated, 6 hypoER-a and 6 control. Age at necropsy and characteristics associated with rhesus endometriosis were comparable between groups. Endometriosis was present in 4/6 hypoER-a females but in only 1/6 controls. HypoER-a animals had endometriosis in the uterus (2 cases), cervix (1 case), fallopian tube (2), ovary (2) and colon (1). The control animal had endometriosis in the uterus. ARID1A was retained in all tissues tested, including cases with endometriosis. WT-1 was positive in both epithelium and stroma for all endometriosis lesions. ER- a was negative in HypoER-a but not control endometriosis; PR was patchy positive in normal endometrium. PAX-8 stained rhesus tissue as would be expected in human analogs. One EnOC was identified in a hypoER-a animal that also had endometriosis. Conclusions: We have successfully created a nonhuman primate model that increases endometriosis penetrance. We also demonstrated parity between rhesus and human female endometriosis and EAOC by gross and histologic examination. Immunohistochemistry demonstrates WT-1 consistently stains endometrial glands and stroma in endometriosis. There was one animal with an EAOC in association with endometriosis. The rhesus macaque poses a higher order animal model for ongoing research in EAOC.

A Novel Predictive Tool for Discriminating Endometriosis Associated Ovarian Cancer from Ovarian Endometrioma: The R2 Predictive Index.

Simple SummaryOvarian Endometrioma (OE) is a precancerous condition for endometriosis-associated ovarian cancer (EAOC). For many clinicians observing OE outpatients, setting the appropriate time for surgery can be a challenge because there is no suggestive milestone. Out of the fear of malignant transformation, many patients have surgery conducted according to respective faculty standards. This study aims to investigate a novel, noninvasive method not requiring an MRI device. This study partly helps to lift the above restrictions, and has the potential to suggest intervention-appropriate timing to the physician.Background: Magnetic resonance (MR) relaxometry provides a noninvasive tool to discriminate between ovarian endometrioma (OE) and endometriosis-associated ovarian cancer (EAOC), with a sensitivity and specificity of 86% and 94%, respectively. MRI models that can measure R2 values are limited, and the R2 values differ between MRI models. This study aims to extract the factors contributing to the R2 value, and to make a formula for estimating the R2 values, and to assess whether the R2 predictive index calculated by the formula could discriminate EAOC from OE. Methods: This retrospective study was conducted at our institution from November 2012 to February 2019. A total of 247 patients were included in this study. Patients with benign ovarian tumors mainly received laparoscopic surgery, and the patients suspected of having malignant tumors underwent laparotomy. Information from a chart review of the patients’ medical records was collected. Results: In the investigative cohort, among potential factors correlated with the R2 value, multiple regression analyses revealed that tumor diameter and CEA could predict the R2 value. In the validation cohort, multivariate analysis confirmed that age, CRP, and the R2 predictive index were the independent factors. Conclusions: The R2 predictive index is useful and valuable to the detection of the malignant transformation of endometrioma.

Oestrogen up-regulates DNMT1 and leads to the hypermethylation of RUNX3 in the malignant transformation of ovarian endometriosis

Research questionWhat is the mechanism of hypermethylation of runt-related transcription factor 3 (RUNX3) in the eutopic endometrium of endometriosis as biomarker in the malignant transformation of endometriosis? DesignMethylation-specific polymerase chain reaction was used to analyse the methylation status of RUNX3 in endometriosis-associated ovarian cancer (EAOC). Primary eutopic endometrial stromal cells (ESC) were isolated from the uteri of patients with ovarian endometriosis. After RUNX3 knockdown by RNA interference technology or ESC treated with oestradiol, the proliferation and invasion ability were evaluated in ESC by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and transwell assays. ResultsThe frequency of methylation of RUNX3 in neoplastic tissue in the EAOC group was significantly higher than that in the ectopic endometrium of the endometriosis group (P < 0.001), and the frequency of methylation of RUNX3 in the eutopic endometrium of the EAOC group was significantly higher than that in the endometriosis group (P < 0.001). However, there was no significant difference in the eutopic endometrium when compared between the endometriosis group and the control endometrium group (P = 0.233). Silencing RUNX3 promoted the proliferation and invasion of ESC (P < 0.001 and P < 0.001). Following intervention with oestrogen, it was observed that the oestradiol group showed higher levels of RUNX3 methylation (P < 0.001) and DNA methyltransferase 1 (DNMT1) mRNA and protein expression (P < 0.001 and P < 0.001), and lower RUNX3 mRNA and protein expression when compared with the ESC group (P < 0.001 and P < 0.001). ConclusionThis study demonstrated that hypermethylation of the RUNX3 was related to the malignant transformation of endometriosis and that this process was related to corresponding changes in the eutopic endometrium. Furthermore, the ‘oestrogen-DNMT1’ signalling pathway may induce the hypermethylation of RUNX3 to promote the malignant transformation of endometriosis.

Immunochemical analysis of iron transporters and M2 macrophages in ovarian endometrioma and clear cell adenocarcinoma.

The association between iron ions and endometriosis-associated ovarian cancer (EAOC) has been previously investigated to elucidate EAOC carcinogenesis; however, the dynamics of iron deposition in the endometrial epithelium and endometrial stroma of ovarian endometrioma (OE) remains unknown. The present study aimed to determine the expression of iron transporters on the cell surface and the distribution of tumor-associated macrophages (TAMs) englobed with iron in the endometrial stroma. The current retrospective study investigated 20 OE and 18 ovarian clear cell adenocarcinoma (CCC) samples, using Perls Prussian blue staining and immunohistochemistry of iron transporters, including divalent metal transporter 1 (DMT1), transferrin receptor (TfR) and ferroportin (FPN). Additionally, samples were stained for CD68, CD11c, CD163 and CD206, and double-immunostained for iron and CD163 to define the distribution of macrophages. Iron transporters were identified on the endometrial epithelium of OE and CCC tumor cells, and TAMs were englobed with iron in the endometrial stroma of OE and CCC. Histological findings revealed DMT1 upregulation in OE and CCC, whereas lower TfR and FPN expression was observed in OE than in CCC. M2 macrophages were englobed with iron ions in the deep layers of the OE and CCC stroma. The endometrial epithelium located in the endometrial stroma of one patient with OE and the endometrial epithelium adjacent to CCC in two patients with CCC stained positive for the tumor proliferation marker Ki67. Epithelium infiltrating the stroma of OE may become the origin of cancer under the influence of M2 macrophages englobed with iron. These findings provide new perspectives on the malignant transformation of OE into EAOC and its possibility as a precancerous index.

Differentiation between endometriosis-associated ovarian cancers and non- endometriosis-associated ovarian cancers based on magnetic resonance imaging.

Endometriosis-associated ovarian cancer (EAOC) patients show different clinical characteristics compared with non-EAOC patients. However, a few studies are focused on the imaging characteristics of EAOC until now. We assessed MRI characteristics in differentiating EAOC and non-EAOC. We retrospectively analyzed clinical and MRI characteristics from 54 patients with 67 lesions diagnosed with primary epithelial ovarian carcinoma at the Third Affiliated Hospital of Guangzhou Medical University between January 2012 and October 2020. We studied MRI findings such as maximum diameter, morphology, configuration, locularity, features of mural nodules, lymphadenopathy, peritoneal implants, the presence of hyperintensity on T1WI, and hypointensity on T2WI. We also studied the clinical characteristics. Significant MRI variables in univariate analysis were selected for subsequent multivariate regression analysis. This study evaluated the diagnostic performance of the significant MRI variables in univariate analysis. We found that the patients with EAOC, compared with those with non-EAOC, were younger, more unilateral, and had earlier FIGO stage. Univariate analysis revealed that morphology, locularity, growth pattern of mural nodules, and hypointensity on T2WI were factors that significantly differed between EAOC and non-EAOC. In the multivariate logistic regression analysis, locularity and hypointensity on T2WI were independent predictors to distinguish EAOC from non-EAOC. EAOC typically presented as a unilocular mass with hypointensity on T2WI in cystic components. MRI could help distinguish EAOC from non-EAOC. MRI is a promising tool for preoperative diagnosis of EAOC.

How Does Endometriosis Lead to Ovarian Cancer? The Molecular Mechanism of Endometriosis-Associated Ovarian Cancer Development.

Simple SummaryDriver gene mutations have been identified in not only various types of endometriosis which are considered the origin of endometriosis-associated ovarian cancer but also the normal endometrium which is considered the origin of endometriosis. We focused on genomic linkage from normal endometrium to ovarian endometriosis and endometriosis-associated ovarian cancer (EAOC) and summarized the current knowledge of the commonality and differentiation of genomic features in the uterine endometrium, endometriosis, and EAOC. In addition, we have proposed molecular mechanism of ovarian carcinogenesis from the normal endometrium via endometriosis based on genomic alterations. This review is expected to contribute to research for the prevention of endometriosis and EAOC.Numerous epidemiological and histopathological studies support the notion that clear cell and endometrioid carcinomas derive from ovarian endometriosis. Accordingly, these histologic types are referred to as “endometriosis-associated ovarian cancer” (EAOC). Although the uterine endometrium is also considered an origin of endometriosis, the molecular mechanism involved in transformation of the uterine endometrium to EAOC via ovarian endometriosis has not yet been clarified. Recent studies based on high-throughput sequencing technology have revealed that cancer-associated gene mutations frequently identified in EAOC may exist in the normal uterine endometrial epithelium and ovarian endometriotic epithelium. The continuum of genomic alterations from the uterine endometrium to endometriosis and EAOC has been described, though the significance of cancer-associated gene mutations in the uterine endometrium or endometriosis remains unclear. In this review, we summarize current knowledge regarding the molecular characteristics of the uterine endometrium, endometriosis, and EAOC and discuss the molecular mechanism of cancer development from the normal endometrium through endometriosis in an effort to prevent EAOC.

The Role of Myeloid-Derived Suppressor Cells (MDSCs) in the Development and/or Progression of Endometriosis-State of the Art.

Endometriosis (EMS) is a common gynecological disease characterized by the presence of endometrial tissue outside the uterus. Approximately 10% of women around the world suffer from this disease. Recent studies suggest that endometriosis has potential to transform into endometriosis-associated ovarian cancer (EAOC). Endometriosis is connected with chronic inflammation and changes in the phenotype, activity, and function of immune cells. The underlying mechanisms include quantitative and functional disturbances of neutrophils, monocytes/macrophages (MO/MA), natural killer cells (NK), and T cells. A few reports have shown that immunosuppressive cells such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) may promote the progression of endometriosis. MDSCs are a heterogeneous population of immature myeloid cells (dendritic cells, granulocytes, and MO/MA precursors), which play an important role in the development of immunological diseases such as chronic inflammation and cancer. The presence of MDSCs in pathological conditions correlates with immunosuppression, angiogenesis, or release of growth factors and cytokines, which promote progression of these diseases. In this paper, we review the impact of MDSCs on different populations of immune cells, focusing on their immunosuppressive role in the immune system, which may be related with the pathogenesis and/or progression of endometriosis and its transformation into ovarian cancer.

Micrornas and The Role of MicroRNAs as a Biomarker in Endometriosis and Endometriosis-associated Epithelial Ovarian Cancers

Micrornas and The Role of MicroRNAs as a Biomarker in Endometriosis and Endometriosis-associated Epithelial Ovarian Cancers

Endometriosis-associated ovarian carcinomas: insights into pathogenesis, diagnostics, and therapeutic targets-a narrative review.

Endometriosis is a benign gynecologic condition affecting up to one woman out of ten of reproductive age. It is defined by the presence of endometrial-like tissue in localizations outside of the uterine cavity. It often causes symptoms such as chronic pain, most frequently associated with the menstrual cycle, and infertility, but may also be oligo- or asymptomatic. There is evidence that some ovarian carcinoma (OC) histotypes, mainly the ovarian clear cell (OCCC) and endometrioid (EnOC) carcinoma, may arise from endometriosis. The most frequent genomic alterations in these carcinomas are mutations in the AT-rich interacting domain containing protein 1A (ARID1A) gene, a subunit of the SWI/SNF chromatin remodeling complex, and alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway, which frequently co-occur. In ARID1A deficient cancers preclinical experimental data suggest different targetable mechanisms including epigenetic regulation, cell cycle, genomic instability, the PI3K/AKT/mTOR pathway, inflammatory pathways, immune modulation, or metabolic alterations as potential precision oncology approaches. Most of these strategies are relying on the concept of synthetic lethality in which tumors deficient in ARID1A are more sensitive to the different compounds. Some of these approaches are currently being or have recently been investigated in early clinical trials. The remarkably frequent occurrence of these mutations in endometriosis-associated ovarian cancer, the occurrence in a relatively young population, and the high proportion of platinum-resistant disease certainly warrants further investigation of precision oncology opportunities in this population. Furthermore, advanced knowledge about oncogenic mutations involved in endometriosis-associated ovarian carcinomas may be potentially useful for early cancer detection. However, this approach may be complicated by the frequent occurrence of somatic mutations in benign endometriotic tissue as recent studies suggest. In this narrative review of the current literature, we will discuss the data available on endometriosis-associated ovarian carcinoma, with special emphasis on epidemiology, diagnosis and molecular changes that could have therapeutic implications and clinical applicability in the future.

Evaluation of PTEN and Ki67 Expression in Typical and Atypical Endometriosis and Endometriosis Associated Ovarian Cancer

Background: Several studies reported that endometriosis is associated with an increased risk of ovarian cancer. Atypical endometriosis is common in patients with endometriosis-associated ovarian, which might be considered as a precancerous lesion. Objectives: This study aimed to assess ki67 and PTEN expression in endometriosis associated ovarian cancer (EAOC), atypical endometriosis, and typical endometriosis. Methods: In this study, all H &amp; E slides of 260 ovarian endometriosis cases were reviewed. And 25 cases were diagnosed with atypical endometriosis. Forty-one typical endometrioses and 24 ovarian cancers with endometriosis were included. We assessed PTEN and Ki67 immunoexpression in epithelial and stromal cells. Results: The prevalence of atypical endometriosis was about 9%. PTEN loss was found in 12 (out of 24 or 50%) of EAOC, 2 (out of 25; 8%) of atypical endometriosis, and none of the typical endometriosis. In all 12 PTEN loss cases, the PTEN loss pattern in endometriosis adjacent to ovarian cancer was similar to that of ovarian cancer. A total of 7.3% of typical endometriosis and 8% atypical endometriosis and 33.3% of EAOC had Ki67 staining in more than 50% of the epithelial component. Both typical and atypical endometriosis showed similar PTEN loss and Ki 67 staining (in more than 50% of the epithelial component) (P value &gt; 0.05), and both of them were different from EAOC (P value &lt; 0.05). Conclusions: The PTEN loss pattern in endometriosis adjacent to ovarian cancer was similar to that of ovarian cancer. The result indicated that PTEN loss could be an early event in the tumor development pathway from endometriosis to ovarian cancer.

Molecular profiling of atypical endometriosis as premalignant lesions of ovarian cancer

Objective: Atypical endometriosis has been reported as a precursor that proceeds to endometriosis-associated ovarian cancer (EAOC). However, the molecular transformation mechanism has not yet been fully understood. The aim of the present study is to identify potential novel disease markers emblematic of the progression of high-risk endometriosis to EAOC.

Atypical endometriosis is related to a higher recurrence rate

ObjectivesThe aims of this study were to evaluate the clinical characteristics and recurrence rate of atypical endometriosis (AE)11AE: Atypical endometriosis, ASRM: American Society of Reproductive Medicine, EAOC: Endometriosis-associated ovarian cancer, RR: Relative risk, TE: Typical endometriosis. compared to typical endometriosis (TE) in addition to the malignant transformation rate among a large cohort. Study designThe medical records of 2681 patients who had undergone surgical treatment of ovarian endometrioma between January 2008 and September 2019 were retrospectively reviewed. The patients were divided into AE (n = 86) and TE (n = 2595) groups. Patients’ characteristics and recurrence rates were evaluated and compared between the two groups. ResultsThe mean size of ovarian cysts was significantly larger in the AE group (7.6 ± 3.5 cm vs 6.7 ± 3.3 cm, p = 0.01) and the proportion of nulliparous women was significantly lower in AE group (65.1 % vs 77.8 %, p = 0.008). Otherwise, there were no statistically significant differences in patient characteristics between the two groups. After Cox regression analyses with IPTW was adjusted, the risk factors for recurrent endometrioma were higher preoperative CA125 level >48 U/mL (hazard ratio [HR] = 2.741; 95 % confidence interval [CI] = 1.517−4.952; p < 0.001), multilocular cyst (HR = 1.909; 95 % CI = 1.128−3.230; p = 0.016), and atypical endometriosis (HR = 2.666; 95 % CI = 1.659−4.284; p < 0.001). The AE group displayed a significantly higher cumulative recurrence rate than the TE group (p = 0.0057, log-rank test). No patients were diagnosed with atypical endometriosis to malignant transformation during the follow-up periods. However, two typical endometriosis patients experienced borderline malignancy and serous carcinoma, respectively. ConclusionRecurrence rates for AE were higher than for TE. Although the AE group included no patient with malignant transformation in this study, considering the higher recurrence as well as the possibility of malignant transformation, long-term close surveillance is warranted.

ARID1A protein expression is retained in ovarian endometriosis with ARID1A loss-of-function mutations: implication for the two-hit hypothesis

ARID1A loss-of-function mutation accompanied by a loss of ARID1A protein expression is considered one of the most important driver events in endometriosis-associated ovarian cancer. Although our recent genomic study clarified that ARID1A loss-of-function mutations were detected in 13% of ovarian endometriosis, an association between the ARID1A mutation status and ARID1A protein expression in ovarian endometriosis remains unclear. We performed immunohistochemical staining for ARID1A in 78 ovarian endometriosis samples and 99 clear cell carcinoma samples. We revealed that not only 70 endometriosis samples without ARID1A mutations but also eight endometriosis samples with ARID1A loss-of-function mutations retained ARID1A protein expression. On the other hand, most of clear cell carcinomas with ARID1A loss-of-function mutations showed a loss of ARID1A protein expression. In particular, clear cell carcinoma samples which harbor multiple ARID1A loss-of-function mutations or both a single ARID1A loss-of-function mutation and ARID1A allelic imbalance lost ARID1A protein expression. However, ARID1A protein expression was retained in seven clear cell carcinomas with ARID1A loss-of-function mutations. These results suggest that a single ARID1A loss-of-function mutation is insufficient for ARID1A loss in ovarian endometriosis and some clear cell carcinoma. Further driver events may be needed for the malignant transformation of ovarian endometriosis with ARID1A loss-of-function mutations.

Endometriosis-Associated Ovarian Cancer: The Origin and Targeted Therapy.

Endometrial cysts (ECs) are thought to be the origin of endometriosis-associated ovarian cancer (EAOC). A hypothesis that the oxidative stress of iron in cysts causes “malignant transformation of ECs” has been proposed, but this has not been verified. Several population-based studies showed that endometriosis was a risk factor but did not reflect the “malignant transformation of ECs”. A review showed that most patients were diagnosed with EAOC early in monitoring following detection of ECs, and that these cases might have been cancer from the start. Epidemiologically, EAOC was reduced by hysterectomy rather than by cystectomy of ECs. Gene mutation analyses identified oncogenic mutations in endometriosis and normal endometrium and revealed that the same mutations were present at different endometriotic lesions. It was also shown that most of the gene mutations found in endometriosis occurred in normal endometrium. Taking together, EAOC might be caused by eutopic endometrial glandular epithelial cells with oncogenic mutations that have undergone menstrual blood reflux and engrafted in the ovary, rather than by low-risk ECs acquiring oncogenic mutations and becoming malignant. This review discusses the mechanisms of EAOC development and targeted therapy based on genetic variation in EAOC with a focus on eutopic endometrium.

Assessing CT imaging features combined with CEA and CA125 levels to identify endometriosis-associated ovarian cancer.

To improve the diagnosis and identification of ovarian clear cell carcinoma (CCC) and ovarian endometrioid carcinoma (EC), we evaluated CT imaging findings and cut-off values for CEA and CA125. The CT features and tumour markers (tumour size, location, morphology, composition, number of cysts, growth pattern of the mural nodules, mural nodule HWR, enhancement of the mural nodules, ascites, complications, CEA level, CA125 level) of 55 tumours in 52 patients with CCC, confirmed by surgery and pathology at the Yunnan Cancer Hospital from January 1, 2012 to December 30, 2018, were compared with those of 41 tumours in 36 patients with EC. All patients had a long history of endometriosis. Statistical analysis was performed using t test, chi-square test, Mann-Whitney U test, univariate analysis, multivariate logistic regression analysis and receiver-operating characteristic (ROC) curves. CCC and EC presented as large oval or irregular mixed cystic-solid masses in the pelvic region, with moderately delayed enhancement of the solid components. There was a statistically significant difference between the number of cysts, the growth pattern of the mural nodules, the presence/absence of ascites, and the levels of CEA and CA125 (P < 0.05). Most CCCs had unilocular cysts, mural nodules that were polypoid structures, and no ascites (46/55, 33/55, 42/55); most ECs had multilocular cysts and broad-based nodular structures and were ascites positive (28/41, 31/41, 21/41). The CEA positive rate was lower in the CCC group than in the EC group (2/52, 3.8% versus 11/36, 30.6%, P < 0.05), and the CA125 positive rate was high in both the CCC and EC groups (44/52, 84.6% versus EC = 35/36, 97.2%, P = 0.118). The ROC curves revealed that when the values of CEA and CA125 were higher than the cut-off values (CEA = 3.270 µg/L, CA125 = 589.400 kU/L), the diagnostic efficiency of CEA was 0.723, and the diagnostic specificity of CEA was as high as 0.903. The number of cysts, growth pattern of the mural nodules, presence/absence of ascites, and levels of CEA and CA125 were useful factors for distinguishing CCC from EC; the best cut-off values of CEA and CA125 for distinguishing CCC from EC were 3.270 and 589.40, respectively. These findings may be helpful for correctly diagnosing and identifying CCC and EC.

Malignant Transformation and Associated Biomarkers of Ovarian Endometriosis: A Narrative Review.

This review focuses on pathogenesis of endometriosis, its possible biomarkers and role in endometriosis-associated ovarian cancer. We analyzed various databases to obtain new insights, theories, and biomarkers associated with endometriosis. There are several theories of endometriosis development and biomarker changes including atypical forms. A number of studies have attempted to establish specific, reliable biomarkers to help diagnose endometriosis and endometriosis-associated diseases on the basis of different pathogenetic pathways. Nevertheless, despite intensive research extending even to the molecular level, the origin, natural history, malignant transformation, and laboratory management of endometriosis and related diseases are not yet clearly defined. Therefore, early laboratory diagnoses of endometriosis, its atypical form, and endometriosis-associated ovarian tumors are important problems that require further study in the context of advanced therapeutic strategies to provide maximal health benefits to patients.

The differential expression of miRNAs between ovarian endometrioma and endometriosis-associated ovarian cancer

BackgroundMicroRNAs (miRNAs) have been implicated to play a vital role in development, differentiation, cell proliferation and apoptosis. However, which miRNAs are actually associated with endometriosis-associated ovarian cancer remains controversial.MethodsSerum and ascites samples were obtained from all patients. Serum samples from 5 cases of ovarian endometrioma and endometriosis-associated ovarian cancer each were submitted for comprehensive miRNA microarray profiling. We investigated the differential expression of miRNAs between the two groups to confirm the pivotal role of miRNAs. Quantitative reverse transcription-polymerase chain reaction validation of five selected miRNAs [miR-92a-3p, miR-486-5p, miR-4484, miR-6821-5p, and miR-7108-5p] was performed, and miR-486-5p expression analysis was followed by proliferation and wound healing assays, depending on the expression of miR-486-5p.ResultmiR-486-5p expression in serum and ascites samples from endometriosis-associated ovarian cancer patients was significantly higher than that from ovarian endometrioma patients. Moreover, the miR-486-5p level in serum and ascites samples was significantly correlated with the severity of the endometriosis. The upregulation of miR-486-5p in immortalized ovarian endometrioma cells significantly increased proliferation and migration. In contrast, the downregulation of miR-486-5p in these cells significantly decreased proliferation and migration.ConclusionmiR-486-5p might function as an oncogenic miRNA in endometriosis-associated ovarian cancer and could be a noninvasive biomarker to prospect the severity of ovarian endometrioma.